US20190231768A1 - Pridopidine for treating drug induced dyskinesias - Google Patents

Pridopidine for treating drug induced dyskinesias Download PDF

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US20190231768A1
US20190231768A1 US16/377,577 US201916377577A US2019231768A1 US 20190231768 A1 US20190231768 A1 US 20190231768A1 US 201916377577 A US201916377577 A US 201916377577A US 2019231768 A1 US2019231768 A1 US 2019231768A1
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pridopidine
administered
levodopa
dyskinesia
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Michal Geva
Aric Orbach
Michael Hayden
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Prilenia Neurotherapeutics Ltd
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Prilenia Therapeutics Development Ltd
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Priority to US16/436,947 priority patent/US11000519B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]

Definitions

  • Dyskinesias are abnormal, involuntary movements which may appear as jerking, twisting or writhing of parts of the body.
  • dyskinesias There are several different types of dyskinesias, which can be categorized as chorea, dystonia, myoclonus, tremor and paroxysmal tardive (late-onset type).
  • Drug-induced movement disorders may be elicited by different pharmaceutical agents, which modulate dopamine neurotransmission as well as other neurotransmission in the central nervous system such as serotonin, adrenaline and acetylcholine neurotransmission.
  • the major groups of drugs responsible for DIMDs include antidepressants, antipsychotics, antiepileptics, antimicrobials, antiarrhythmics, mood stabilisers and gastrointestinal drugs, among others. These movement disorders include, without limitation, parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics.
  • Parkinson's disease is a degenerative disorder characterized by the loss of substantia nigra pars compacta dopaminergic neurons and the subsequent loss of dopaminergic input to the striatum. As the degenerative process evolves, dopamine replacement therapy becomes necessary to help alleviate motor dysfunction.
  • Dyskinesias are common in Parkinson's disease (PD) and can be separated into a) dyskinesias resulting from the disease process itself, and b) dyskinesias that are the side-effect of levodopa medication given to treat symptoms of PD (Levodopa-Induced Dyskinesia, LID) (Cubo 2001).
  • L-DOPA Levodopa
  • PD-LID dopamine-replacement therapy in PD
  • Other dopamine agonist therapies may induce dyskinesia in PD patients.
  • the levodopa-induced dyskinesias occur in the majority of the PD patients and initially are mild, progressing to a complex and severe disorder that interferes with motor function, speech, coordination and social activity. LID can adversely affect the quality of life for Parkinson's disease patients.
  • Peak-dose dyskinesias are the most prevalent type of dyskinesia. They occur during peaks of levodopa-derived dopamine in the brain, when the patient is otherwise experiencing a beneficial response (the ‘on’ state). Peak dose dyskinesias worsen with increases in dopaminergic therapy and lessen with reductions in dopaminergic therapy. Some patients exhibit diphasic dyskinesia, which occurs when levodopa-derived dopamine concentrations are increasing or decreasing and the patient is shifting between ‘on’ and ‘off” states.
  • the therapeutic and preventative strategies for LID include using a lower dosage of levodopa, employing other dopamine agonists as initial therapy in Parkinson's disease, amantadine, atypical neuroleptics, and neurosurgery.
  • pridopidine to reduce motor complications of L-DOPA in PD was reported using the 6-OHDA-lesioned rat model (Ponten 2013). The data from that rat 6-OHDA study suggests that low doses of pridopidine, up to about 67.5 mg bid may be efficacious against PD-LID.
  • Pridopidine (formerly ACR16, Huntexil®, TV-7820) is a drug in development for the treatment of patients with Huntington's disease.
  • the chemical name of pridopidine base is 4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine, and its Chemical Registry Number is CAS 346688-38-8 (CSID:7971505, 2016).
  • the Chemical Registry number of pridopidine hydrochloride is 882737-42-0 (CSID:25948790 2016).
  • Pridopidine demonstrates a complex binding profile with high affinity binding to the sigma-1 receptor (ciR, or SIR) (Internal studies; Sahlholm 2013,) and low affinity binding to several other CNS targets, including receptors for dopamine, serotonin, 5-HT1A, 5-HT2A and 5-HT7; adrenergic alpha-1, adrenergic alpha-2A and alpha-2C receptors, dopamine D3 and dopamine D2 (D2R) receptors; and muscarinic M2 and histamine H3 receptors (Internal studies; Ponten 2013).
  • ciR sigma-1 receptor
  • SIR sigma-1 receptor
  • Pridopidine has been shown to modulate motor activity by either suppressing hyperactivity or enhancing hypoactivity.
  • the neuroprotective properties of pridopidine are suggested to be attributed to its high affinity to the SIR, while the motor activity of pridopidine may be mediated primarily by its moderate-affinity targets, including antagonistic activity at the dopamine D2 receptor (Ponten 2010, Sahlholm 2015).
  • the SIR is an endoplasmic reticulum (ER) chaperone protein which is implicated in cellular differentiation, neuroplasticity, neuroprotection and cognitive function in the brain.
  • BDNF brain-derived neurotrophic factor
  • DIR dopamine receptor 1
  • GR glucocorticoid receptor
  • Akt serine-threonine kinase protein kinase B
  • PI3K phosphoinositide 3-kinase
  • the present invention is based at least in part on evidence from in vivo studies that high doses of pridopidine are efficacious in treating symptoms of drug induced dyskinesias, including PD-LID.
  • the present invention provides a method of treating LID in a subject with PD comprising administering to the subject an amount of pridopidine effective to treat the LID in the subject.
  • the present invention also provides a method of treating LID in a subject with parkinsonism other than PD comprising administering to the subject an amount of pridopidine effective to treat the LID in the subject.
  • the present invention also provides a method for treating dyskinesia induced by a drug other than levodopa, for example an anti-depressant or an anti-psychotic comprising administering to the subject an amount of pridopidine effective to treat the dyskinesia in the subject.
  • a drug other than levodopa for example an anti-depressant or an anti-psychotic comprising administering to the subject an amount of pridopidine effective to treat the dyskinesia in the subject.
  • the present invention additionally provides a method of treating a subject afflicted with a drug-induced movement disorder (DIMD).
  • the invention further provides a method for treatment of a DIMD in a subject in need thereof comprising periodically administering to the subject an amount of pridopidine effective to treat the DIMD.
  • the invention also provides pridopidine for use in treating drug-induced movement disorder (DIMD) in a subject in need thereof.
  • the DIMD comprises dyskinesia.
  • the dyskinesia is levodopa-induced dyskinesia (LID).
  • the DIMD is induced by a drug selected from an antidepressant, an antipsychotic, an antiepileptic, an antimicrobial, an antiarrhythmic, a mood stabilizer, a gastrointestinal drug or any combination thereof.
  • a drug selected from an antidepressant, an antipsychotic, an antiepileptic, an antimicrobial, an antiarrhythmic, a mood stabilizer, a gastrointestinal drug or any combination thereof.
  • Certain selective serotonin reuptake inhibitors (SSRI) are known to induce DIMD (Gerber 1998, incorporated herein in its entirety by reference).
  • the DIMD is selected from parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics.
  • the invention further provides a method of treating a subject afflicted with a side effect of levodopa treatment comprising administering to the subject an amount of pridopidine effective to treat the subject.
  • the invention provides pridopidine for use in treating a side effect of levodopa treatment in a subject in need thereof.
  • This invention further provides a method of treating a human subject afflicted with a levodopa induced dyskinesia comprising periodically administering to the subject an amount of levodopa and an amount of pridopidine or a salt thereof, wherein the amounts when taken together are effective to treat the human subject.
  • pridopidine in combination with levodopa for use in treating levodopa induced dyskinesia in a subject in need thereof.
  • the subject is afflicted with parkinsonism.
  • the subject is a patient afflicted with Parkinson's disease.
  • the invention further provides a method of treating a subject at risk of developing a drug-induced movement disorder, including levodopa-induced dyskinesia, comprising administering to the subject an amount of pridopidine effective to delay the onset of LID or reduce the risk of developing LID.
  • a drug-induced movement disorder including levodopa-induced dyskinesia
  • the amount of pridopidine administered is greater than 100 mg/day up to 400 mg/day. In certain embodiments, the amount of pridopidine administered is 112.5 mg/day, 125 mg/day, 135 mg/day, 150 mg/day, 175 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, or 400 mg/day.
  • the AUC0-inf 24 achieved is 12,000 h*ng/ml to 60,000 h*ng/ml, or 20,000 h*ng/ml-60,000 h*ng/ml, or 25,000 h*ng/ml-60,000 h*ng/ml or at least 29,000 h*ng/ml up to about 60,000 h*ng/mi.
  • This invention also provides a package comprising (a) a first pharmaceutical composition comprising an amount of levodopa and a pharmaceutically acceptable carrier, (b) a second pharmaceutical composition comprising an amount of pridopidine and a pharmaceutically acceptable carrier.
  • the package also comprises (c) instructions for use of the first and second pharmaceutical compositions together to treat a human subject afflicted with LID or DIMD.
  • the pridopidine is provided as pridopidine base.
  • the pridopidine is provided as a pridopidine salt, e.g. pridopidine HCl.
  • This invention additionally provides use of an amount of levodopa and an amount of pridopidine in the preparation of a combination for treating a human subject afflicted with a levodopa induced dyskinesia wherein the levodopa or pharmaceutically acceptable salt thereof and the pridopidine are administered simultaneously or contemporaneously.
  • This invention additionally provides use of an amount of amantadine, or levodopa and amantadine, and an amount of pridopidine in the preparation of a combination for treating a human subject afflicted with a levodopa induced dyskinesia wherein the levodopa, or levodopa and amantadine, and the pridopidine are administered simultaneously or contemporaneously.
  • This invention also provides a pharmaceutical composition comprising an amount of levodopa for use in treating a subject afflicted with levodopa induced dyskinesia as an add-on therapy or in combination with pridopidine by periodically administering the pharmaceutical composition and the pridopidine to the subject.
  • This invention also provides a pharmaceutical composition comprising an amount of pridopidine for use treating a subject afflicted with levodopa induced dyskinesia as an add-on therapy or in combination with levodopa and/or amantadine by periodically administering the pharmaceutical composition to the subject.
  • the dyskinesia in a subject afflicted with PD is quantified by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score, wherein an increase in the MDS-UPDRS score represents progression of Parkinson's disease symptoms, and the increment of the increase in total UPDRS score over a period of time represents the rate of progression of Parkinson's disease symptoms (Goetz 2007, Goetz 2008a, the entire contents of which are hereby incorporated by reference).
  • the dyskinesia in a subject afflicted with PD is quantified using the PD Home Diary scale.
  • the dyskinesia in a subject not afflicted with PD is quantified by, for example, the Unified Dyskinesia Rating Scale (UdysRS) or AIMS rating scale (Goetz 2008b, Ecdeu 1976, the entire contents of which are hereby incorporated by reference).
  • UdysRS Unified Dyskinesia Rating Scale
  • AIMS AIMS rating scale
  • FIGS. 1-3 show the effect of pridopidine in historic studies of Huntington's disease.
  • FIGS. 1A and 1B Graphs showing the effect of 45 mg bid pridopidine on Total Motor Score (TMS), full analysis set from MermaiHD ( FIG. 1A ) and HART ( FIG. 1B ) studies, respectively.
  • TMS Total Motor Score
  • FIG. 1A full analysis set from MermaiHD
  • FIG. 1B HART
  • FIG. 2 Bar graph showing the effect of 45 mg bid or 112.5 mg bid pridopidine on change from baseline in Total Motor Score (TMS) in early stage HD Patients (baseline TFC ⁇ 11) at week 52 in the PRIDE-HD study. A decrease in TMS from baseline indicates improvement (table below the graph).
  • TMS Total Motor Score
  • FIG. 3 bar graph showing the effect of 45 mg bid or 112.5 mg bid pridopidine on change from baseline in Total Functional Capacity (TFC), full analysis, at week 52 by treatment group in the PRIDE-HD study. An increase in TFC from baseline indicates improvement (table below the graph).
  • FIG. 4 Reproduction of a PET scan showing levels of SIR occupancy by pridopidine in the brain of healthy volunteers before (upper panel) and after (lower panel) a single dose of 45 mg pridopidine.
  • FIGS. 5-10 show the effect of pridopidine in combination with a high L-DOPA dose in a MPTP-lesioned non-human primate (NHP) model with established motor complications in two studies.
  • the figures provide data showing that pridopidine reduced L-DOPA induced dyskinesia, including choreiform and dystonic dyskinesia evoked by high-dose L-DOPA without affecting the beneficial anti-parkinsonian effects of L-DOPA.
  • FIG. 5A Graph showing dyskinesia (time course 0-6 hr) (study 2): Pridopidine reduces established dyskinesia evoked by high L-DOPA.
  • Y axis is severity of dyskinesia, X axis shows time course, 0-6 hr.
  • FIG. 5B Bar graph showing dyskinesia (0-2 hr accumulated) (study 2): Pridopidine reduces established dyskinesia evoked by high dose L-DOPA.
  • Y axis is severity of dyskinesia
  • X axis shows pridopidine doses.
  • FIG. 6A Graph showing Parkinsonian disability (time course 0-6 hr): Pridopidine does not reduce the anti-parkinsonian benefit of L-DOPA (study 2).
  • Y axis is severity of parkinsonian disability, X axis shows time course in hours.
  • Triangles vehicle/vehicle (no L-DOPA and no pridopidine) treated animals; circles: L-DOPA/vehicle or L-DOPA/pridopidine treated animals.
  • FIG. 6B Bar graph showing Parkinsonian disability (0-2 hr accumulated) Pridopidine does not reduce the anti-parkinsonian benefit of L-DOPA (study 2).
  • Y axis is severity of parkinsonian disability, X axis shows pridopidine doses.
  • FIG. 7A Graph showing dyskinesia (time course 0-6 hr) (study 1): Pridopidine reduces established dyskinesia evoked by high dose L-DOPA. Y axis is severity of dyskinesia, X axis shows time course in hours.
  • FIG. 7B Bar graph showing dyskinesia (0-2 hr accumulated) (study 1): Pridopidine reduces established dyskinesia evoked by high dose L-DOPA. Y axis is severity of dyskinesia, X axis shows pridopidine doses.
  • FIG. 8A Graph showing Parkinsonian disability (time course 0-6 hr): Pridopidine does not reduce the anti-parkinsonian benefit of L-DOPA (study 1).
  • Y axis is severity of parkinsonism (parkinsonian disability), X axis shows time course in hours.
  • FIG. 8B Bar graph showing Parkinsonian disability (0-2 hr accumulated): Pridopidine does not reduce the anti-parkinsonian benefit of L-DOPA (study 1).
  • Y axis is severity parkinsonian disability, X axis shows pridopidine doses.
  • FIG. 9A Graph showing that pridopidine reduces L-DOPA induced dystonia (study 2).
  • Y axis is severity of dystonia, X axis time course 0-6 hours.
  • FIG. 9B Bar graph showing pridopidine effect on L-DOPA induced dystonia (0-2 hr accumulated) (study 2): Pridopidine reduces established dystonia evoked by high dose L-DOPA.
  • Y axis is severity of dystonia
  • X axis shows pridopidine doses.
  • FIG. 9C Bar graph showing pridopidine effect on L-DOPA induced dystonia (0-2 hr accumulated) (study 1): Pridopidine reduces established dystonia evoked by high dose L-DOPA. Y axis is severity of dystonia, X axis shows pridopidine doses.
  • FIG. 9D Bar graph showing pridopidine effect on L-DOPA induced chorea (0-2 hr accumulated) (study 1): Pridopidine reduces chorea evoked by high dose L-DOPA. Y axis is severity of chorea, X axis shows pridopidine doses.
  • FIG. 10 Bar graph showing the effects of pridopidine on duration and quality of on-time (study 2).
  • the present invention provides a method of treating a subject afflicted with a drug-induced movement disorder (DIMD) comprising periodically administering to the subject an amount of pridopidine effective to treat the subject.
  • the invention further provides a method for the treatment of a DIMD comprising periodically administering to a subject in need thereof an amount of pridopidine effective to treat the DIMD.
  • the DIMD comprises dyskinesia.
  • the dyskinesia is Levodopa-Induced Dyskinesia (LID).
  • the invention also provides a method of treating a subject afflicted with a side effect of levodopa treatment comprising administering to the subject an amount of pridopidine effective to treat the subject.
  • treating comprises reducing a side effect of levodopa.
  • the side effect is dyskinesia.
  • the subject is a patient afflicted with parkinsonism.
  • the subject is a Parkinson's disease patient.
  • the subject is an advanced stage Parkinson's disease patient.
  • the subject is a patient afflicted with parkinsonism other than Parkinson's disease.
  • the subject is concurrently being treated with levodopa.
  • the amount of pridopidine and the levodopa are administered simultaneously. In another embodiment, the amount of pridopidine and the levodopa are co-formulated. In another embodiment, the amount of pridopidine and the levodopa are administered sequentially and in separate pharmaceutical formulations.
  • the amount of pridopidine is effective to alleviate or reduce a symptom associated with the levodopa treatment.
  • the symptom is dyskinesia, abnormal movements, myoclonic jerks, irregular movements of extremities, gait, facial grimacing, ataxia, inability to sustain motor act, hand movement or balance.
  • the symptom is choreiform peak dose dyskinesia, or dystonic peak dose dyskinesia.
  • the symptom is bad quality on-time evoked by levodopa.
  • the administration of pridopidine improves the symptom of the levodopa induced dyskinesia by at least 8%, by at least 10%, by at least 15%, by at least 20%, by at least 30% or by at least 50% as measured by the Unified Dyskinesia Rating Scale (UDysRS) (Unified Dyskinesia Rating Scale (UDysRS) 2008, the entire content of which is hereby incorporated by reference).
  • UDysRS Unified Dyskinesia Rating Scale
  • the anti-parkinsonian effect of levodopa is not affected by the amount of pridopidine.
  • the dyskinesia in the subject is assessed by one or more of the following rating scales: UDysRS, UPDRS or AIMS (Unified Dyskinesia Rating Scale (UDysRS) 2008; Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. 2003, Ecdeu 1976, the entire content of each of which is hereby incorporated by reference).
  • the patient had a UDysRS score or UPDRS score of 10 or greater at baseline.
  • the DIMD is induced by a drug selected from an antidepressant, an antipsychotic, an antiepileptic, an antimicrobial, an antiarrhythmic, a mood stabilizer, a gastrointestinal drug or any combination thereof.
  • the DIMD may be selected from parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics.
  • the DIMD is parkinsonism.
  • the DIMD is tardive dyskinesia.
  • the DIMD is drug-induced dystonia.
  • the DIMD is tremor.
  • the DIMD is akathisia.
  • the DIMD is athetosis.
  • the DID is myoclonus.
  • the DIMD is tics.
  • the pridopidine is administered via oral administration. In another embodiment, the pridopidine is administered once or twice daily. In another embodiment, pridopidine is administered twice daily. In another embodiment, pridopidine is administered thrice daily. In another embodiment, the pridopidine is a pridopidine base. In another embodiment, the pridopidine is a pridopidine salt. In another embodiment, the pridopidine salt is provided as pridopidine hydrochloride (pridopidine HCl).
  • the amount of pridopidine administered to a subject in need thereof is 112.5 mg/day, 125 mg/day, 135 mg/day, 150 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 375 mg/day or 400 mg/day.
  • the amount of pridopidine administered is from above 100 mg per day to 400 mg per day.
  • the amount of pridopidine administered is from above 200 mg per day to 350 mg per day.
  • the amount of pridopidine administered is from above 100 mg per day to 350 mg per day.
  • the amount of pridopidine administered is more than 100 mg per day to 400 mg per day. In another embodiment, the amount of pridopidine administered is 200 mg per day. In another embodiment, the amount of pridopidine administered is 300 mg per day. In another embodiment, the amount of pridopidine administered is 350 mg per day. In some embodiments, the amount of pridopidine is administered once daily. In some embodiments, the amount of pridopidine is administered twice daily. In some embodiments, the amount of pridopidine administered is 75 mg bid (thrice daily), 90 mg bid, 100 mg bid, or 125 mg bid.
  • the amount of pridopidine administered is 100 mg bid (twice daily), 125 mg bid, 150 mg bid, 175 mg bid, or 200 mg bid.
  • the pridopidine is administered as pridopidine HCl, twice daily.
  • the amount of pridopidine administered is from about 75 mg bid to about 200 mg bid. In one embodiment, the amount of pridopidine administered is from about 80 mg bid to about 200 mg bid. In one embodiment, the amount of pridopidine administered is from about 90 mg bid to about 200 mg bid. In one embodiment, the amount of pridopidine administered is from about 100 mg bid to about 200 mg bid. In one embodiment, the amount of pridopidine administered is from about 125 mg bid to about 200 mg bid. In one embodiment, the amount of pridopidine administered is from about 150 mg bid to about 200 mg bid. In one embodiment, the amount of pridopidine administered is from about 175 mg bid to about 200 mg bid.
  • the amount of pridopidine administered is from about 75 mg bid to about 175 mg bid. In one embodiment, the amount of pridopidine administered is from about 75 mg bid to about 150 mg bid. In one embodiment, the amount of pridopidine administered is from about 75 mg bid to about 125 mg bid. In one embodiment, the amount of pridopidine administered is from about 75 mg bid to about 100 mg bid.
  • the amount of pridopidine administered is from about 90 mg bid to about 175 mg bid. In one embodiment, the amount of pridopidine administered is from about 100 mg bid to about 175 mg bid. In one embodiment, the amount of pridopidine administered is from about 100 mg bid to about 150 mg bid. In one embodiment, the amount of pridopidine administered is from about 125 mg bid to about 150 mg bid. In one embodiment, the amount of pridopidine administered is from about 125 mg bid to about 175 mg bid. In one embodiment, the amount of pridopidine administered is from about 150 mg bid to about 200 mg bid.
  • the pridopidine is administered about 100 mg bid. In one embodiment, the pridopidine is administered about 125 mg bid. In one embodiment, the pridopidine is administered about 150 mg bid. In one embodiment, the pridopidine is administered about 175 mg bid. In one embodiment, the pridopidine is administered about 200 mg bid.
  • the pridopidine is administered orally. In one embodiment, the pridopidine is administered about 100 mg bid orally. In one embodiment, the pridopidine is administered about 125 mg bid orally. In one embodiment, the pridopidine is administered about 150 mg bid orally. In one embodiment, the pridopidine is administered about 175 mg bid orally. In one embodiment, the pridopidine is administered about 200 mg bid orally.
  • pridopidine is administered at a daily dose of about 200 mg given in the form of pridopidine salt.
  • the 200 mg of the daily dose refers to 200 mg of pridopidine in its neutral/base form.
  • pridopidine is administered at a daily dose of about 225 mg given in the form of pridopidine salt.
  • pridopidine is administered at a daily dose of about 250 mg given in the form of pridopidine salt. In embodiments of the method or use for treating LID in PD patients, pridopidine is administered at a daily dose of about 275 mg given in the form of pridopidine salt. In embodiments of the method or use for treating LID in PD patients, pridopidine is administered at a daily dose of 300 mg given in the form of pridopidine salt. In embodiments of the method or use for treating LID in PD patients, pridopidine is administered at a daily dose of about 325 mg given in the form of pridopidine salt.
  • pridopidine is administered at a daily dose of about 350 mg given in the form of pridopidine salt. In embodiments of the method or use for treating LID in PD patients, pridopidine is administered at a daily dose of about 375 mg given in the form of pridopidine salt. In embodiments of the method or use for treating LID in PD patients, pridopidine is administered at a daily dose of about 400 mg given in the form of pridopidine salt. In preferred embodiments of the method or use for treating LID in PD patients, the specified dosage of pridopidine is administered in two equal doses.
  • the AUC0-24 achieved is about 25,000 h*ng/ml to about 60,000 h*ng/ml.
  • pridopidine is administered to a subject in need thereof in an amount to achieve an AUC 0-24 plasma level of greater than 12,000 h*ng/ml to about 60,000 h*ng/ml, 20,000 h*ng/ml to 60,000 h*ng/ml, 25,000 h*ng/ml to 60,000 h*ng/ml, 29,000 h*ng/ml to 60,000 h*ng/ml, 15,000 h*ng/ml to 45,000 h*ng/ml, 15,000 h*ng/ml to 40,000 h*ng/ml, 20,000 h*ng/ml to 55,000 h*ng/ml, 20,000 h*ng/ml to 50,000 h*ng/ml, 20,000 h*ng/ml to 45,000 h*ng/ml, 20,000 h*ng/ml to 40,000 h*ng/ml, 20,000 h*ng/ml, 20,000 h*ng/ml to 40,000
  • the method further comprises administering to the subject a therapeutically effective amount of levodopa.
  • the amount of pridopidine administered to the subject is 22.5 mg/day, 45 mg, 67.5 mg/day, 75 mg/day, 90 mg/day, 100 mg/day, 112.5 mg/day, 125 mg/day, 135 mg/day, 150 mg/day, 180 mg per day, 225 mg/day, 250 mg/day, 270 mg/day, 275 mg/day, 300 mg/day, 350 mg/day, 360 mg/day, 375 mg/day or 400 mg/day.
  • pridopidine is administered at a daily dose of 45 mg given in the form of pridopidine salt. In embodiments of the method or use for treating DIMD other than LID in PD patients, pridopidine is administered at a daily dose of 90 mg given in the form of pridopidine salt. In embodiments of the method or use for treating DIMD other than LID in PD patients, pridopidine is administered at a daily dose of 135 mg given in the form of pridopidine salt.
  • pridopidine is administered at a daily dose of 180 mg given in the form of pridopidine salt. In embodiments of the method or use for treating DIMD other than LID in PD patients, pridopidine is administered at a daily dose of 200 mg given in the form of pridopidine salt. In embodiments of the method or use for treating DIMD other than LID in PD patients, pridopidine is administered at a daily dose of 225 mg given in the form of pridopidine salt.
  • pridopidine is administered at a daily dose of 250 mg given in the form of pridopidine salt. In embodiments of the method or use for treating DIMD other than LID in PD patients, pridopidine is administered at a daily dose of 300 mg given in the form of pridopidine salt. In embodiments of the method or use for treating DIMD other than LID in PD patients, pridopidine is administered at a daily dose of 350 mg given in the form of pridopidine salt.
  • pridopidine is administered at a daily dose of 400 mg given in the form of pridopidine salt.
  • the daily dose of pridopidine is administered in two equal doses.
  • the method further comprises administering to the subject a therapeutically effective amount of a second compound which is levodopa and/or amantadine.
  • the subject is administered pridopidine and levodopa.
  • the subject is administered pridopidine and amantadine.
  • the subject is administered pridopidine, levodopa and amantadine.
  • the pridopidine and the second compound e.g. levodopa, amantadine or levodopa and amantadine
  • the pridopidine and the second compound are administered in more than one unit.
  • the second compound is amantadine.
  • the amount of amantadine is 10 mg-400 mg.
  • the amount of amantadine is 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 100 mg, 137 mg, 150 mg, 200 mg, 250 mg, 274 mg, 300 mg, 350 mg, or 400 mg per day in one dose or divided doses.
  • the amantadine is administered orally.
  • the second compound is levodopa.
  • the amount of levodopa may be administered at a dose of, for example, 250 mg-6000 mg per day in one or more divided doses.
  • the amount of Levodopa is 250 mg, 300 mg, 500 mg, 750 mg, 1,000 mg, 1,500 mg, 2,000 mg, 2,500 mg, 3,000 mg, 3,500 mg, 4,000 mg, 4,500 mg, 5,000 mg, 5,500 mg, or 6,000 mg per day in one dose or divided doses.
  • the amount of pridopidine and the amount of the second compound are administered simultaneously.
  • the administration of the second compound substantially precedes the administration of pridopidine.
  • the administration of pridopidine substantially precedes the administration of the second compound.
  • the subject is receiving amantadine therapy or levodopa therapy prior to initiating pridopidine therapy.
  • the subject is receiving amantadine therapy or levodopa therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating pridopidine therapy.
  • the subject is receiving pridopidine therapy prior to initiating receiving amantadine therapy or levodopa therapy.
  • the subject is receiving pridopidine therapy for at least 24 weeks, 28 weeks, 48 weeks, or 52 weeks prior to initiating receiving amantadine therapy or levodopa therapy.
  • each of the amount of the second compound when taken alone and the amount of pridopidine when taken alone is effective to treat the subject. In another embodiment, either the amount of the second compound when taken alone, the amount of pridopidine when taken alone, or each such amount when taken alone is not effective to treat the subject. In another embodiment, either the amount of the second compound when taken alone, the amount of pridopidine when taken alone, or each such amount when taken alone is less effective to treat the subject.
  • the pridopidine is administered adjunctively to the second compound. In other embodiments, the second compound is administered adjunctively to the pridopidine.
  • a loading dose of an amount different from the intended dose is administered for a period of time at the start of the periodic administration.
  • the loading dose is double the amount of the intended dose.
  • the loading dose is half the amount of the intended dose.
  • This invention provides a method of treating a human subject afflicted with a levodopa induced dyskinesia comprising periodically administering to the subject an amount of levodopa and an amount of pridopidine, wherein the amounts when taken together are effective to treat the human subject.
  • the levodopa induced dyskinesia is a peak dose dyskinesia. In another embodiment, the levodopa induced dyskinesia is diphasic dyskinesia.
  • the amount of levodopa and the amount of pridopidine when taken together are effective to reduce a symptom of the levodopa induced dyskinesia in the human subject.
  • the symptom is abnormal movements, myoclonic jerks, irregular movements of extremities, gait, facial grimacing, ataxia, inability to sustain motor act, hand movement or balance.
  • the subject is afflicted with PD and the subject's motor function is assessed using the total motor score (TMS) or the modified motor score (mMS) derived from the Unified Parkinson's Disease Rating Scale (UPDRS).
  • the patient had an mMS score of 10 or greater at baseline.
  • the subject is afflicted with parkinsonism other than PD parkinsonism and the subject's motor function is assessed by the UDysRS.
  • the administration of levodopa and pridopidine improves a symptom of the levodopa induced dyskinesia by at least 10%. In an embodiment of the present invention, the administration of levodopa and pridopidine improves a symptom of the levodopa induced dyskinesia by at least 20%. In another embodiment, the administration of levodopa and pridopidine improves a symptom of the levodopa induced dyskinesia by at least 30%. In another embodiment, the administration of levodopa and pridopidine improves a symptom of the levodopa induced dyskinesia by at least 50%.
  • the administration of levodopa and pridopidine improves a symptom of the levodopa induced dyskinesia by more than 100%. In another embodiment, the administration of levodopa and pridopidine improves a symptom of the levodopa induced dyskinesia by more than 300%.
  • the human subject is receiving levodopa therapy prior to initiating pridopidine therapy.
  • the administration of levodopa and/or amantadine precedes the administration of pridopidine by at least one week, at least one month, at least three months, at least six months, or at least one year.
  • the levodopa is administered via oral administration. In another embodiment, the levodopa is administered daily. In another embodiment, the levodopa is administered more often than once daily. In another embodiment, the levodopa is administered less often than once daily.
  • the amount of levodopa administered is about 50 mg to 8,000 mg/day.
  • pridopidine is administered orally.
  • pridopidine is administered through a nasal, inhalation, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route.
  • the pridopidine is administered daily.
  • the pridopidine is administered more often than once daily.
  • the administration of pridopidine is administered twice a day.
  • the pridopidine is administered less often than once daily.
  • the amount of pridopidine administered is greater than 100 to 1000 mg/day. In another embodiment, the amount of pridopidine administered is between 45-400 mg/day. In another embodiment, the amount of pridopidine administered is 112.5-400 mg/day. In another embodiment, the amount of pridopidine administered is 180-400 mg/day. In another embodiment, the amount of pridopidine administered is 150-400 mg/day. In another embodiment, the amount of pridopidine administered is 150-350 mg/day. In another embodiment, the amount of pridopidine administered is 180-400 mg/day.
  • the amount of pridopidine administered is 200-400 mg/day. In another embodiment, the amount of pridopidine administered is 180 mg/day. In another embodiment, the amount of pridopidine administered is 200 mg/day. In another embodiment, the amount of pridopidine administered is 225 mg/day. In another embodiment, the amount of pridopidine administered is 250 mg/day. In another embodiment, the amount of pridopidine administered is 300 mg/day. In another embodiment, the amount of pridopidine administered is 350 mg/day. In another embodiment, the amount of pridopidine administered is 400 mg/day.
  • the amount of pridopidine administered is 10-1,000 mg/day. In another embodiment, the amount of pridopidine administered is 45-400 mg/day. In another embodiment, the amount of pridopidine administered is 20-180 mg/day. In another embodiment, the amount of pridopidine administered is 50-180 mg/day. In another embodiment, the amount of pridopidine administered is 30-120 mg/day. In another embodiment, the amount of pridopidine administered is 150-1000 mg/day. In another embodiment, the amount of pridopidine administered is 180-1000 mg/day.
  • the amount of pridopidine administered is 150-400 mg/day. In another embodiment, the amount of pridopidine administered is 150-350 mg/day. In another embodiment, the amount of pridopidine administered is 180 mg/day. In another embodiment, the amount of pridopidine administered is 90 mg/day. In another embodiment, the amount of pridopidine administered is about 45 mg/day. In another embodiment, the amount of pridopidine administered is about 90 mg/day.
  • the method further comprises administration of a second compound which is an antidepressant, a psychotropic drug, an antipsychotic, amisulpride, haloperidol, olanzapine, risperidone, sulpiride, or tiapride.
  • a second compound which is an antidepressant, a psychotropic drug, an antipsychotic, amisulpride, haloperidol, olanzapine, risperidone, sulpiride, or tiapride.
  • the periodic administration of the second compound and pridopidine continues for at least 3 days.
  • the periodic administration of the second compound and pridopidine continues for more than 30 days.
  • the periodic administration of the second compound and pridopidine continues for more than 42 days.
  • the periodic administration of the second compound and pridopidine continues for 8 weeks or more.
  • the periodic administration of the second compound and pridopidine continues for at least 12 weeks. In another embodiment, the periodic administration of the second compound and pridopidine continues for at least 24 weeks. In another embodiment, the periodic administration of the second compound and pridopidine continues for more than 24 weeks. In yet another embodiment, the periodic administration of the second compound and pridopidine continues for 6 months, or 12 months or more.
  • This invention also provides a package comprising (a) a first pharmaceutical composition comprising an amount of levodopa and a pharmaceutically acceptable carrier; (b) a second pharmaceutical composition comprising an amount of pridopidine and a pharmaceutically acceptable carrier; and optionally (c) instructions for use of the first and second pharmaceutical compositions together to treat a human subject afflicted with levodopa induced dyskinesia.
  • the pridopidine is pridopidine HCl or other pharmaceutically acceptable salt.
  • the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical composition are in tablet form.
  • the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical composition are in the form of an aerosol or inhalable powder.
  • the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical composition are in liquid form.
  • the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical composition are in solid form.
  • the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical composition are in capsule form.
  • the amount of pridopidine in the second composition is 45 to 400 mg. In another embodiment, the amount of pridopidine in the second composition is 75-400 mg. In another embodiment, the amount of pridopidine in the second composition is 90-400 mg. In another embodiment, the amount of pridopidine in the second composition is 112.5-400 mg. In another embodiment, the amount of pridopidine in the second composition is 150-350 mg. In another embodiment, the amount of pridopidine in the second composition is 180-400 mg. In another embodiment, the amount of pridopidine in the second composition is 225-400 mg. In another embodiment, the amount of pridopidine in the second composition is 45 mg.
  • the amount of pridopidine in the second composition is 75 mg. In another embodiment, the amount of pridopidine in the second composition is about 90 mg. In another embodiment, the amount of pridopidine in the second composition is about 112.5 mg. In another embodiment, the amount of pridopidine in the second composition is 125 mg. In another embodiment, the amount of pridopidine in the second composition is 150 mg. In yet another embodiment, the amount of pridopidine in the second composition is 200 mg.
  • This invention also provides amantadine for use as an add-on therapy or in combination with pridopidine in treating a human subject afflicted with a neurodegenerative disorder.
  • This invention also provides a pharmaceutical composition comprising an amount of levodopa and/or amantadine and an amount of pridopidine.
  • the pharmaceutical composition is in the form of an aerosol or inhalable powder.
  • the pharmaceutical composition is in liquid form.
  • the pharmaceutical composition is in solid form.
  • the pharmaceutical composition is in capsule form.
  • the pharmaceutical composition is in tablet form.
  • the daily amount of pridopidine administered is greater than 100 mg and up to 400 mg. In another embodiment, the amount of pridopidine administered is 45-400 mg. In another embodiment, the amount of pridopidine administered is 110-400 mg. In another embodiment, the daily amount of pridopidine administered is 135-400 mg. In another embodiment, the daily amount of pridopidine administered is 250-400 mg. In another embodiment, the daily amount of pridopidine is 135-180 mg. In another embodiment, the daily amount of pridopidine administered is 180-350 mg. In another embodiment, the daily amount of pridopidine administered is 135 mg.
  • the daily amount of pridopidine administered is 180 mg. In another embodiment, the daily amount of pridopidine is 200 mg. In another embodiment, the daily amount of pridopidine administered is 225 mg. In another embodiment, the daily amount of pridopidine administered is 250 mg. In another embodiment, the daily amount of pridopidine administered is 300 mg. In another embodiment, the daily amount of pridopidine administered is 350 mg. In another embodiment, the daily amount of pridopidine administered is 400 mg.
  • This invention also provides use of an amount of levodopa and/or amantadine and an amount of pridopidine in the preparation of a combination for treating a human subject afflicted with a levodopa induced dyskinesia wherein the levodopa and/or amantadine or pharmaceutically acceptable salt thereof and the pridopidine are administered simultaneously or contemporaneously.
  • This invention also provides a pharmaceutical composition comprising an amount of levodopa and/or amantadine for use in treating a subject afflicted with levodopa induced dyskinesia as an add-on therapy or in combination with pridopidine by periodically administering the pharmaceutical composition and the pridopidine to the subject.
  • This invention also provides a pharmaceutical composition comprising an amount of pridopidine for use treating a subject afflicted with levodopa induced dyskinesia as an add-on therapy or in combination with levodopa and/or amantadine by periodically administering the pharmaceutical composition and the levodopa and/or amantadine to the subject.
  • each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments.
  • the elements recited in the method embodiments can be used in the pharmaceutical composition, package, and use embodiments described herein and vice versa.
  • an amount effective to achieve an end means the quantity of a component that is sufficient to yield an indicated therapeutic response.
  • an amount effective to reduce a symptom of LID in a Parkinson's disease (PD) patient is administered without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this disclosure.
  • compositions, uses and methods can be used to treat levodopa-induced dyskinesia (LID).
  • LID can be present in PD patients who have been on levodopa for extended periods of time.
  • Off-time is when a PD patient's levodopa medication is no longer working well for them, and at least some of their Parkinson's symptoms have returned. The return of PD symptoms may include e.g.; slowness, stiffness or tremor; and sometimes total (akinesia) or partial (bradykinesia) immobility.
  • On-time is the time when a PD patient's levodopa medication is having benefit, and their Parkinson's symptoms are generally well controlled.
  • Bad quality on-time is period of time when a PD patient's medication is not effective, for example, the patient is medicated and afflicted with disabling dyskinesia.
  • dyskinesia Three forms of dyskinesia have been classified on the basis of their course and presentation following treatment with levodopa; i) peak-dose dyskinesia (the most common form of LID; it correlates with high L-DOPA plasma level); ii) diphasic dyskinesia (occurs with rising and falling plasma levodopa levels; this form is usually dystonic or ballistic; does not respond to L-DOPA reduction); and iii) off-period dystonia (correlated to the akinesia that occurs before the full effect of L-DOPA sets in, when the plasma levels of L-DOPA are low) (Bargiotas 2013).
  • peak-dose dyskinesia the most common form of LID; it correlates with high L-DOPA plasma level
  • diphasic dyskinesia occurs with rising and falling plasma levodopa levels; this form is usually dystonic or ballistic; does not respond to L-DOPA reduction
  • to “treat” or “treating” encompasses reducing a symptom, inducing inhibition, regression, or stasis of the disorder and/or disease.
  • “inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject.
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • Subject includes humans.
  • the terms “human,” “patient,” and “subject” are used interchangeably herein unless the context clearly indicates the contrary (e.g. in reference to healthy human volunteers).
  • the subject is a human adult.
  • the subject is a human adult having a mass of 70 kg.
  • administering to the subject or “administering to the (human) patient” means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition.
  • Oral administration is one way of administering the instant compounds to the subject. The administration can be periodic administration.
  • Periodic administration means repeated/recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times a week and so on, etc.
  • “adjunctively” means treatment with or administration of an additional compound, with a primary compound, for example for increasing the efficacy or safety of the primary compound or for facilitating its activity.
  • pridopidine means pridopidine base or a pharmaceutically acceptable salt thereof, as well as its analogues or combination of pridopidine and its analogues or derivatives, for example deuterium-enriched version of pridopidine and salts. Examples of deuterium-enriched pridopidine and salts and their methods of preparation may be found in U.S. Application Publication Nos. 2013-0197031, 2016-0166559 and 2016-0095847, the entire content of each of which is hereby incorporated by reference.
  • acid addition salts of pridopidine include, but is not limited to, the hydrochloride, the hydrobromide, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like.
  • pridopidine is a pharmaceutically acceptable salt, such as the HCl salt or tartrate salt.
  • the pridopidine is in the form of its hydrochloride salt.
  • analogues of pridopidine are represented by the following structures:
  • the pridopidine is in the form of its hydrochloride salt.
  • Pridopidine mixtures, compositions, the process for the manufacture thereof, the use thereof for treatment of various conditions, and the corresponding dosages and regimens are described in, e.g., PCT International Application Publication Nos. WO 2001/46145, WO 2011/107583, WO 2006/040155, U.S. Patent Application Publication No. 2011/0206782, U.S. Patent Application Publication No. 2010/0197712, the entire content of each of which is hereby incorporated by reference.
  • an “amount” or “dose” of pridopidine as measured in milligrams refers to the milligrams of underivatized pridopidine base present in a preparation, dose or daily dose, regardless of the form of the preparation.
  • a “dose of 200 mg pridopidine” means the amount of pridopidine in a preparation is sufficient to provide 200 mg of underivatized pridopidine base having a naturally occurring isotope distribution, regardless of the form of the preparation.
  • a salt e.g.
  • the mass of the salt form necessary to provide a dose of 200 mg underivatized pridopidine base would be greater than 200 mg due to the presence of the additional salt ion.
  • the mass of the derivatized form necessary to provide a dose of 200 mg underivatized pridopidine base having a naturally occurring isotope distribution would be greater than 200 mg due to the presence of the additional deuterium.
  • the factor for converting mass of pridopidine HCl to mass of pridopidine base is 0.885 (e.g. 1 mg pridopidine HCl ⁇ 0.885 mg pridopidine base). Accordingly, 112.99 mg/day dose of pridopidine HCl is equivalent to a 100 mg dose of pridopidine base.
  • any range disclosed herein it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention.
  • 0.01 mg 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.
  • any range of time disclosed herein i.e. weeks, months, or years
  • it is meant that all lengths of time of days and/or weeks within the range are specifically disclosed as part of the invention.
  • 3-6 months means that 3 months and 1 day, 3 months and 1 week, and 4 months are included as embodiments of the invention.
  • levodopa means L-3,4-dihydroxyphenylalanine (levodopa or L-DOPA) levodopa or a pharmaceutically acceptable salt thereof, as well as derivatives.
  • Cmax refers to the maximum plasma, serum or blood concentration of a drug, following administration of the drug, e.g. pridopidine, or a pharmaceutically acceptable salt thereof.
  • Cmin refers to the minimum plasma, serum or blood concentration of a drug, following administration of the drug, e.g. pridopidine, or a pharmaceutically acceptable salt thereof.
  • Tmax refers to the time required to reach the maximal plasma, serum or blood concentration (“Cmax”) of the drug, following administration of the drug, e.g. pridopidine, or a pharmaceutically acceptable salt thereof.
  • AUC refers to the area under the plasma, serum or blood concentration versus time curve.
  • AUC0-t refers to the area under the plasma, serum or blood concentration versus time curve wherein t (hours) is the last measured time point.
  • AUCinfinity refers to the area under the plasma, serum or blood concentration versus time curve extrapolated to infinity.
  • AUC 24,ss refers to area under the concentration-time curve from 0 to 24 hours at steady state. Units are presented as h*ng/ml.
  • the active compounds for use according to the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically acceptable salts, and pre- or prodrug forms of the compound of the invention.
  • a “salt thereof” is a salt of the instant compound which has been modified by making acid or base salts of the compound.
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compound of the present invention suitable for pharmaceutical use.
  • Pharmaceutically acceptable salts may be formed by procedures well known and described in the art. One means of preparing such a salt is by treating a compound of the present invention with an inorganic base.
  • Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride, the hydrobromide, the L-tartrate, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzene-sulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methane-sulphonate, the naphthalene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate, the toluene-p-sulphonate, and the like.
  • the non-toxic inorganic and organic acid addition salts such as the hydrochloride
  • pridopidine is provided as a pharmaceutically acceptable salt, such as the HCl salt or tartrate salt.
  • the pridopidine is in the form of its hydrochloride salt.
  • “Deuterium-enriched” means that the abundance of deuterium at any relevant site of the compound is more than the abundance of deuterium naturally occurring at that site in an amount of the compound. The naturally occurring distribution of deuterium is about 0.0156%.
  • the abundance of deuterium at any of its relevant sites is more than 0.0156% and can range from more than 0.0156% to 100%, for example 50%, 60%, 70%, 75%, 8-%, 85%, 90%, 95%, 98% or 100%.
  • Deuterium-enriched compounds may be obtained by exchanging hydrogen with deuterium or synthesizing the compound with deuterium-enriched starting materials.
  • the methods, uses, packages and kits include deuterated pridopidine.
  • the compounds for use according to the invention may be administered in the form of the raw compound, it is preferred to introduce the active ingredients, optionally in the form of physiologically acceptable salts, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • the invention provides pharmaceutical compositions comprising the active compounds or pharmaceutically acceptable salts or derivatives thereof, together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and/or prophylactic ingredients know and used in the art.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • the pharmaceutical composition of the invention may be administered by any convenient route, which suits the desired therapy.
  • Preferred routes of administration include oral administration, in particular in tablet, in capsule, in dragé, in powder, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection, for example infusion.
  • the pharmaceutical composition of the invention can be manufactured by the skilled person by use of standard methods and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.
  • the combination of the invention may be formulated for its simultaneous or contemporaneous administration, with at least a pharmaceutically acceptable carrier, additive, adjuvant or vehicle. This has the implication that the combination of two or three or more active compounds may be administered:
  • “combination” means an assemblage of reagents for use in therapy either by simultaneous or contemporaneous administration.
  • Simultaneous administration refers to administration of an admixture (whether a true mixture, a suspension, an emulsion or other physical combination) of pridopidine and a second compound (for example, levodopa, amantadine or combination of levodopa and amantadine).
  • the combination may be the admixture or separate containers of pridopidine the second compound that are combined just prior to administration.
  • Contemporaneous administration, or concomitant administration refers to the separate administration of pridopidine and the second compound at the same time, or at times sufficiently close together that a synergistic activity relative to the activity of either pridopidine alone the second compound alone is observed or in close enough temporal proximately to allow the individual therapeutic effects of each agent to overlap.
  • additive-on or “add-on therapy” means a therapy, wherein the subject receiving the therapy begins a first treatment regimen of one or more reagents prior to beginning a second treatment regimen of one or more different reagents in addition to the first treatment regimen, so that not all of the reagents used in the therapy are started at the same time.
  • adding pridopidine or pridopidine and amantadine therapy to a Parkinson's disease patient already receiving levodopa therapy The FDA has recently approved extended release amantadine (GocovriTM; previously ADS-5102) for treating LID in patients with Parkinson's disease.
  • amantadine means amantadine or a pharmaceutically acceptable salt thereof, as well as derivatives, for example deuterium-enriched version of amantadine and salts. Amantadine is descried in Prescribers' Digital Reference which is hereby incorporated by reference (for example, Amantadine PDR 2017). Amantadine as used herein refers to amantadine base or any pharmaceutically acceptable salt thereof.
  • an extended release formulation of amantadine may be administered to the subject in the evening and pridopidine may be given twice or three times during the day, for example morning and afternoon.
  • immediate release formulations of amantadine are administered in the morning and afternoon and pridopidine is administered in the morning, afternoon and early evening.
  • levodopa is administered to the subject.
  • Parkinson's disease is a progressive disorder of the nervous system that affects movement.
  • PD is the second most common progressive neurodegenerative disorder affecting older American adults and is predicted to increase in prevalence as the United States population ages.
  • the disease is a result of pathophysiologic loss or degeneration of dopaminergic neurons in the substantia nigra (SN) of the midbrain and the development of neuronal Lewy Bodies.
  • SN substantia nigra
  • PD is characterized by both motor and non-motor symptoms.
  • PD patients classically display rest tremor, rigidity, bradykinesia, and stooping posture, but can also exhibit neurobehavioral disorders (depression, anxiety), cognitive impairment (dementia), and autonomic dysfunction (e.g., orthostasis and hyperhidrosis).
  • the underlying molecular pathogenesis involves multiple pathways and mechanisms: ⁇ -synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation.
  • Dyskinesia refers to hyperkinetic movement disorders in which a variety of abnormal involuntary movements can manifest as single or multiple phenomenologies, which are typically present during wakefulness and cease during sleep.
  • dyskinesia can be a feature that is associated with PD and that differentiates PD from other disorders, where they are much less common.
  • Dyskinesia and other features of PD are measured as part of the Unified Parkinson's Disease Rating Scale (UPDRS) (Goetz 2007; Movement Disorder Society Task Force 2003; the entire contents of which are hereby incorporated by reference).
  • UPDRS Unified Parkinson's Disease Rating Scale
  • the dopamine (DA) precursor L-DOPA (also known as levodopa) has been the most effective treatment for PD for over 40 years, however the response to this treatment changes with disease progression and most patients develop dyskinesias and motor fluctuations, resulting from L-DOPA, within a few years of therapy.
  • LID Levodopa-Induced Dyskinesia
  • the features of Levodopa-Induced Dyskinesia (LID) are different from those of PD dyskinesia and include chorea, dystonia, akathisia, athetosis and tics.
  • Dyskinesia in PD can sometimes, in a general sense, refer to the movement disorder associated with PD.
  • LID is related to administration of L-DOPA and incorporates chorea, dystonia, akathisia, athetosis, tics, myoclonus.
  • UDysRS Unified Dyskinesia Rating Scale
  • LID The mechanisms underlying development of LID involve interplay between progressive degeneration of neurons in the basal ganglia and chronic dopaminergic stimulation by levodopa treatment. Mechanisms underlying LID are not completely understood, however both pre- and postsynaptic disturbances of dopamine (DA) transmission are involved. Presynaptic factors contribute to generating fluctuating levels of levodopa and DA in the brain and include loss of Dopamine Transporters (DAT) and loss of physiological DA storage and release sites. Postsynaptic molecular mechanisms include changes in dopamine receptor trafficking, signaling and supersensitivity, structural and molecular changes in striatal neurons and altered activity in the basal ganglia.
  • DAT Dopamine Transporters
  • Non-dopaminergic modulatory systems such as the glutamatergic system, serotonergic neurons as well as other neuromodulators (Noradrenaline, acetylcholine, opioids and cannabinoids) also play a role in LID.
  • Additional functional and structural changes involved in the pathogenesis of dyskinesia include modulation of vascular endothelial growth factor expression level by astrocytes and over activation of the adenosine A2A receptors. Changes in the extracellular levels of glutamate and altered levels of the glutamate transporter gene expression have been observed in basal ganglia structure of dyskinetic animals. Taken together, these functional alterations point towards a complex multi factorial mechanism behind the generation and expression of dyskinesia which could explain the difficulty of managing these motor complications (reviewed in Daneault 2013).
  • DIMD drug-induced movement disorders
  • drugs responsible for DIMDs include antidepressants, antipsychotics (neuroleptics), antiepileptics, antimicrobials, antiarrhythmics, mood stabilizers and gastrointestinal drugs among others.
  • These movement disorders can include: Parkinsonism, Tardive dyskinesia, Chorea, Dystonia, Tremor, Akathisia, Myoclonus or Tics.
  • LID refers to an abnormal muscular activity disorder that results from levodopa therapy, the disorder being characterized by either disordered or excessive movement (referred to as “hyperkinesia” or “dyskinesia”), slowness, or a lack of movement (referred to as “hypokinesia,” “bradykinesia,” or “akinesia”).
  • LID includes any involuntary movement that results from levodopa therapy, such as chorea, ballism, dystonia, athetosis, tic, or myoclonus.
  • levodopa-induced dyskinesia are chorea and dystonia, which often coexist. (Johnston 2001). Based on their relationship with levodopa dosing, levodopa-induced dyskinesias are classified as peak-dose, diphasic, off state, on state, and yo yo dyskinesias. Peak-dose dyskinesias are the most common forms of LID and are related to peak plasma (and possibly high striatal) levels of levodopa. They involve the head, trunk, and limbs, and sometimes respiratory muscles. Dose reduction can ameliorate them, frequently at the cost of deterioration of parkinsonism.
  • Peak-dose dyskinesias are usually choreiform, though in the later stages dystonia can superimpose. Diphasic dyskinesias develop when plasma levodopa levels are rising or falling, but not with the peak levels. They are also called D-I-D (dyskinesia-improvement-dyskinesia). D-I-D are commonly dystonic in nature, though chorea or mixed pattern may occur. They do not respond to levodopa dose reduction and may rather improve with high dose of levodopa. “Off” state dystonias occur when plasma levodopa levels are low (for example, in the morning). They are usually pure dystonia occurring as painful spasms in one foot. They respond to levodopa therapy. Rare forms of LID include “on” state dystonias (occurring during higher levels of levodopa) and yo-yo dyskinesia (completely unpredictable pattern).
  • DIMD Drug-Induced Movement Disorders
  • Drug-induced dystonia is a twisting movement or abnormal posture (or a combination thereof) may manifest as acute or tardive involuntary limb movements, facial grimacing, cervical dystonia, oculogyric crisis, rhythmic tongue protrusion, jaw opening or closing, spasmodic dysphonia, and, rarely, stridor and dyspnea.
  • Drug-induced tardive dyskinesia includes involuntary movements that resemble multiple movement disorders.
  • the term tardive means “late” to indicate that the condition occurs sometime after drug exposure, and the terms dyskinesia and dystonia describe the types of movements involved.
  • Parkinsonid means “late” to indicate that the condition occurs sometime after drug exposure
  • dyskinesia and dystonia describe the types of movements involved.
  • neuroleptics which act by blocking dopamine receptors (e.g., amoxapine, chlorpromazine, fluphenazine, haloperidol, one notable exception being clozapine)
  • results in hypersensitivity or up-regulation of dopamine receptors in the basal ganglia of the brain see e.g., Andrews, Can J Psych 39:576).
  • Drug-induced akathisia (restlessness and characteristic movements of the legs) is one of the most disagreeable extrapyramidal side effects often caused by use of antipsychotic and antidepressant drugs.
  • Drug-induced Tourette syndrome is a neurological disorder with repetitive, involuntary movements or vocalizations. These involuntary movements are known as tics. Some of the most common tics are eye blinking, among other eye movements and facial grimacing, shoulder shrugging, and head or shoulder jerking. Some of these can be combined with one another to make more complex tics. Some tics involve self-harm but only in a small percentage (10% to 15%) of individuals
  • Non-limiting examples of drugs that can induce movement disorders include any one of (US trade name in parentheses): acetohenazine (Tindal), amoxapine (Asendin), chlorpromazine (Thorazine), fluphenazine (Permitil, Prolixin), haloperidol (Haldol), loxapine (Loxitane, Daxolin), mesoridazine (Serentil), metaclopramide (Reglan), molinndone (Lindone, Moban), perphanzine (Trilafrom, Triavil), piperacetazine (Quide), prochlorperzine (Compazine, Combid), promazine (Sparine), promethazine (Phenergan), thiethylperazine (Torecan), thioridazine (Mellaril), thiothixene (Navane), trifluoperazine (Stelazine), triflupromazine (US trade name in
  • pridopidine refers to the quantity of pridopidine (or the quantities of pridopidine and a second compound) that is sufficient to yield a desired therapeutic response.
  • pridopidine is administered with acetophenazine (Tindal). In some embodiments, pridopidine is administered with amoxapine (Asendin). In some embodiments, pridopidine is administered with chlorpromazine (Thorazine). In some embodiments, pridopidine is administered with fluphenazine (Permitil, Prolixin). In some embodiments, pridopidine is administered with haloperidol (Haldol). In some embodiments, pridopidine is administered with loxapine (Loxitane, Daxolin). In some embodiments, pridopidine is administered with mesoridazine (Serentil).
  • pridopidine is administered with metaclopramide (Reglan). In some embodiments, pridopidine is administered with molinndone (Lindone, Moban). In some embodiments, pridopidine is administered with perphanzine (Trilafrom, Triavil). In some embodiments, pridopidine is administered with piperacetazine (Quide). In some embodiments, pridopidine is administered with prochlorperzine (Compazine, Combid). In some embodiments, pridopidine is administered with promazine (Sparine). In some embodiments, pridopidine is administered with promethazine (Phenergan).
  • Regular metaclopramide
  • pridopidine is administered with molinndone (Lindone, Moban). In some embodiments, pridopidine is administered with perphanzine (Trilafrom, Triavil). In some embodiments, pridopidine is administered with piperacetazine (Quide
  • pridopidine is administered with thiethylperazine (Torecan). In some embodiments, pridopidine is administered with thioridazine (Mellaril). In some embodiments, pridopidine is administered with thiothixene (Navane). In some embodiments, pridopidine is administered with trifluoperazine (Stelazine). In some embodiments, pridopidine is administered with triflupromazine (Vesprin). In some embodiments, pridopidine is administered with trimeprazine (Temaril).
  • UDysRS Unified Dyskinesia Rating Scale
  • the UDysRS measures the intensity of dyskinesias in different body areas, the degree of impairment caused by dyskinesias when patients perform tasks of daily living, and the patient's perception of disability from dyskinesias.
  • On-Dyskinesia refers to the choreic and dystonic movements described to the patient as “jerking or twisting movements that occur when your medicine is working.”
  • Off-Dystonia is described to the patient as “spasms or cramps that can be painful and occur when Parkinson's disease medications are not taken or are not working”.
  • the MDS-UPDRS, Movement Disorder Society-Sponsored revision of the Unified Parkinson's Disease Rating Scale is another example of a rating scale often used in evaluating a PD patient's symptoms pre and post treatment (Goetz, 2008a; the entire content of which is hereby incorporated by reference).
  • the Total Unified Parkinson's Disease Rating Scale (UPDRS) score represents the level or severity of Parkinson's disease symptoms. It is used for measuring the change from baseline in efficacy variables during the treatment. UPDRS consists of a four-part test. A total of 42 items are included in Parts I-IV. Each item in parts I-Ill receives a score ranging from 0 to 4 where 0 represents the absence of impairment and 4 represents the highest degree of impairment. The sum of Parts I-IV at each study visit provides a Total UPDRS score. Parts I, II and IV are historical information. Part I is designed to rate mentation, behavior and mood (items 1-4).
  • Part II (items 5-17) relates to Activities of Daily Living and refers to speech, swallowing, handwriting and the like.
  • Part II (items 18-31) is a motor examination at the time of a visit and relates to facial expressions, tremor, rigidity and the like.
  • Part IV (Items 32-42) relates to complications of the therapy and include questions relating to the disability and pain of the dyskinesia, on-off periods and the like.
  • AIMS Abnormal Involuntary Movement Scale
  • CGIC Clinical Global Impression of Change
  • CDQ-24 modified Craniocervical Dystonia
  • UPDRS Ultrasound Rating scales including UPDRS, AIMS and UDysRS are available, for example, through the International Parkinson and Movement Disorder Society globally and from persons skilled in the art of movement disorder.
  • the patient and independent rater may be independently blinded or not blinded. In some embodiment, patient and rater are blinded.
  • a “symptom” associated with a levodopa induced dyskinesia includes any clinical or laboratory manifestation associated with the levodopa induced dyskinesia and is not limited to what the subject can feel or observe.
  • a symptom of LID includes, but is not limited to involuntary movement, such as chorea, ballism, dystonia, tic, or myoclonus.
  • the subject may experience one or more of the symptoms. For example, chorea and dystonia often coexist. Other symptoms may become apparent including tics or stereotypy.
  • “Improvement of” or “improving” or “ameliorating” a symptom as used herein refers to a favorable change in the patient's symptom as compared to baseline or as compared to a control subject not receiving the treatment.
  • “substantially precedes administration” means that the administration of one agent precedes another agent; and the two agents are not administered simultaneously or contemporaneously.
  • a “pharmaceutically acceptable carrier” refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. It can be a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the subject.
  • 0.1-2.5 mg/day includes 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, etc. up to 2.5 mg/day.
  • a method of treating a subject afflicted with a drug-induced movement disorder comprising periodically administering to the subject an amount of pridopidine effective to treat the subject.
  • DIMD drug-induced movement disorder
  • treating comprises reducing a side effect of levodopa.
  • DIMD is induced by a drug selected from an antidepressant, an antipsychotic, an antiepileptic, an antimicrobial, an antiarrhythmic, a mood stabilizer, a gastrointestinal drug or any combination thereof.
  • DIMD is selected from parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics.
  • a pharmaceutical composition comprising an effective amount of pridopidine for use in treating a subject afflicted with a drug-induced movement disorder (DIMD).
  • DIMD drug-induced movement disorder
  • pridopidine for the manufacture of a medicament for use in treating a subject afflicted with a drug-induced movement disorder (DIMD).
  • DIMD drug-induced movement disorder
  • a package comprising:
  • a) a pharmaceutical composition comprising an amount of pridopidine; and optionally
  • a therapeutic package for dispensing to, or for use in dispensing to, a subject which comprises:
  • each such unit dose comprising an amount of pridopidine thereof, wherein the amount of said pridopidine in said unit dose is effective, upon administration to said subject, to treat a drug-induced movement disorder (DIMD) in the subject, and
  • DIMD drug-induced movement disorder
  • a finished pharmaceutical container therefor said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of a subject afflicted with the DIMD.
  • a package comprising:
  • a) a first pharmaceutical composition comprising an amount of pridopidine and a pharmaceutically acceptable carrier
  • a second pharmaceutical composition comprising an amount of a second compound and a pharmaceutically acceptable carrier; and optionally
  • a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with a drug-induced movement disorder which comprises:
  • each such unit dose comprising:
  • a finished pharmaceutical container therefor said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.
  • a pharmaceutical composition comprising an amount of pridopidine and an amount of amantadine.
  • a pharmaceutical composition comprising an amount of pridopidine for use in treating a subject afflicted with a drug-induced movement disorder (DIMD) as an add-on therapy to second compound.
  • DIMD drug-induced movement disorder
  • Pridopidine has been evaluated for the treatment of motor symptoms in patients with Huntington's Disease (HD), in three large scale clinical trials.
  • Upper grey line placebo, lower black line 45 mg bid pridopidine) de Yebenes 2011; Huntington Study Group HART investigators 2013; the entire contents of which are hereby incorporated by reference).
  • the PRIDE-HD study was conducted as an exploratory, phase 2 dose-ranging, 52-week, double-blind, placebo-controlled study, to evaluate efficacy and safety of pridopidine at doses higher than those used in prior studies, ranging from 45 mg to 112.5 mg bid and further disclosed in PCT Patent Publication No. WO2014/205229 and WO2018/039477.
  • SIR and D2R dopamine-2 receptor
  • the tracer (S)-( ⁇ )-[18F]fluspidine (Brust 2014) was used to evaluate SIR target engagement and occupancy and [18F]fallypride (Slifstein 2010) tracer was used to evaluate D2R engagement and occupancy.
  • Pridopidine doses of 0.5, 1, 5, 22.5, 45 and 90 mg were used to evaluate occupancy of the SIR, and 90 mg was used for D2R occupancy.
  • the study consisted of a screening period of up to 8 weeks prior to first dosing of tracer, including a Ti three-dimensional magnetization-prepared rapid acquisition gradient echo (MPRAGE 3D) magnetic resonance imaging (MRI) scan (visit 1), a study period of up to 4 weeks (including visits 2 and 3), and a follow-up visit (visit 4).
  • MPRAGE 3D magnetic resonance imaging
  • MRI magnetic resonance imaging
  • the subjects underwent a baseline PET investigation (PET session 1) at visit 2, and subsequently a post-treatment PET investigation (PET session 2) following a single oral dose of pridopidine at visit 3.
  • PET session 1 a baseline PET investigation
  • PET session 2 post-treatment PET investigation
  • Each dose cohort comprised up to 4 subjects. Although every subject of each dose cohort was expected to receive the same dose, it was also possible to change the dose level within a cohort due to the adaptive design of the study.
  • the results of the imaging analysis show a S1R occupancy in healthy volunteers of almost 100% with 45 and 90 mg pridopidine, and a SIR occupancy of approximately 40% at doses as low as 1 mg pridopidine. This is an unexpectedly high SIR occupancy at even very low doses.
  • FIG. 4 is a PET scan showing levels of SIR occupancy by pridopidine in the brain of healthy volunteers before (bright tissue, upper panel) and after (lower panel) a single dose of 45 mg pridopidine.
  • pridopidine in complex pathologies such as DIMD may be mediated by its interaction with both the SIRs and the low affinity dopamine receptors (i.e. D2R).
  • pridopidine at 45 mg bid selectively occupies the SIR and not the low affinity targets.
  • pridopidine doses equivalent to about 100 mg-175 mg bid (200-350 mg/day) were tested in non-human primates (NHP). These doses reached AUC 0-24 levels above 29,000 h*ng/ml, thereby targeting the low affinity receptors.
  • pridopidine to reduce motor complications of L-DOPA in PD was reported using the 6-OHDA-lesioned rat model (Ponten 2013).
  • Pridopidine dosed at 25 ⁇ mole/kg (corresponding to 8 mg/kg), decreased the L-DOPA-induced sensitization of contraversive-rotation while showing no decrease in the anti-parkinsonian benefit of L-DOPA.
  • a pridopidine dose of 8 mg/kg in the rat results in AUC 0-24 levels of ⁇ 12000 h*ng/ml which corresponds closely to the AUC 0-24 levels reached by the 67.5 mg bid dose in humans (12865 h*ng/ml).
  • the human 67.5 mg bid dose is estimated, based on human PET data and PK profile of pridopidine, to exhibit effects similar to the 45 mg bid dose and fully occupy the S1Rs with minimal occupancy of the dopamine receptors (DARs).
  • DARs dopamine receptors
  • PK pharmacokinetic
  • Study 1 evaluated the effects of pridopidine at 7 and 20 mg/kg in combination with L-DOPA on MPTP-lesioned macaques.
  • pridopidine at 15, 20 and 30 mg/kg in combination with L-DOPA was tested.
  • pridopidine was administered 1 hour before L-DOPA.
  • pridopidine was administered 2 hours before L-DOPA.
  • Pridopidine hydrochloride (HCl) (4-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride), MW 317.87 g/mol, highly soluble in water was obtained.
  • HCl 3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride
  • pridopidine was formulated in sterile water with no correction made for the hydrochloride salt. Pridopidine was administered at a dose-volume of 1 ml/kg body weight.
  • In vitro binding studies were performed at Eurofins Panlabs Taiwan, Ltd to evaluate IC50/Ki values for affinity of pridopidine to sites including ⁇ 1, ⁇ 2, adrenergic ⁇ 2C, ⁇ 2A, dopamine D3, dopamine D2, serotoninergic 5-HT1A, 5-HT2A, 5-HT7, histamine H3, muscarinic M2.
  • NMDA, 5-HT6 and tachykinin NK1 receptors along with the dopamine transporter (DAT), norepinephrine transporter (NET) and serotonin transporter (SERT).
  • DAT dopamine transporter
  • NET norepinephrine transporter
  • SERT serotonin transporter
  • the specific ligand binding to the receptors was defined as the difference between the total binding and the nonspecific binding determined in the presence of an excess of unlabeled ligand.
  • IC50 values were determined by a non-linear, least squares regression analysis using MathIQTM (ID Business Solutions Ltd., UK).
  • Inhibition constants (Ki) values were calculated using the equation of Cheng and Prusoff 16 using the observed IC50 of the tested compound, the concentration of radio ligand employed in the assay, and the historical values for the KD of the ligand (obtained experimentally at Eurofins Panlabs, Inc.).
  • Hill coefficient (nH) defining the slope of the competitive binding curve, was calculated using MathIQTM. Hill coefficients significantly different than 1.0, may suggest that the binding displacement does not follow the laws of mass action with a single binding site.
  • Blood sampling On days of treatment, administration and plasma sampling, macaques were transferred from their home cages and seated in individual primate chairs.
  • Blood samples 0.5 ml
  • K2-EDTA tubes Becton Dickinson, Mississauga, ON, Canada
  • Bioanalysis of pridopidine in macaque plasma Pridopidine and its internal standard, 4-(3-methylsulfonyl)phenyl)-1-(propyld7)-piperidin-1-ium chloride, were extracted from EDTA plasma by liquid-liquid extraction into acetonitrile as follows: An aliquot of 20 ⁇ l of plasma was added to 80 ⁇ l of acetonitrile containing 1-10 ng/ml of the internal standard (IS). After centrifuging at 13000 rpm for 8 min, 70 ⁇ l of supernatant was isolated and added to 70 ⁇ l of sterile water. Finally, an aliquot of 1-10 ⁇ l of the mixture was injected into the LC-MS/MS system.
  • the linearity was from 2 ng/ml to 1000 ng/ml with LLOQ of 2 ng/ml.
  • Accuracy values for pridopidine was lower than 15% for all calibration curves and for >75% of each QC sample sets.
  • All PK parameters were calculated per individual animal according to nominal time, that is, within +5% from schedule time-point by non-compartmental modelling for extravascular administration using WinNonlin 6.3. Below the Limit of Quantification (BLQ) value at time 0 or at a sampling time before the first quantifiable concentration, were treated as zero. BLQ values occurring at the end of the profile were treated as missing. Terminal elimination half-life (t 1/2 ) was calculated as ln(2)/ ⁇ z.
  • C max The maximum observed plasma concentration
  • t max time to reach C max
  • AUC 0-24 Area under the plasma concentration-versus-time curve from time 0 to 24 h post dose
  • pridopidine The pharmacokinetic profile of pridopidine was also characterized in plasma samples collected at multiple time-points up to 24 h after oral administration. These and other PK data across rodent and primate species were used to assess the relationship between plasma pridopidine levels and central SIR/D2/3R receptor occupancy.
  • MPTP administration and development of motor complications Animals received once-daily subcutaneous injection of MPTP (0.2 mg/kg in 0.9% sterile-saline, Sigma-Aldrich, Oakville, ON, Canada) for 8-30 days. A parkinsonian syndrome was then allowed to develop over at least a 90-day period, during which time additional MPTP administrations were given as necessary, until animals reached moderate to marked levels of disability. Average cumulative MPTP dose was 33.3 mg. MPTP lesions were allowed to stabilize for a minimum of a further 60-day prior to commencing induction of L-DOPA-induced motor complications.
  • LID including both choreiform and dystonic dyskinesia
  • chronic L-DOPA treatment 25 mg/kg, MadoparTM, Roche, L-DOPA: benserazide, ratio 4:1
  • animals were acclimatized to the experimental setting, trained to provide blood samples (while restrained in chair) and to receive administration of treatment by oral, intravenous or subcutaneous routes.
  • L-DOPA dose-finding Dose-finding observations were conducted to identify a dose of L-DOPA (LDh) intended to produce optimal anti-parkinsonian actions but which was compromised by disabling dyskinesia (range 30-35 mg/kg, mean 32.1 mg/kg). The response to this dose of L-DOPA was assessed to ensure stability and reproducibility within each animal on successive L-DOPA administrations.
  • LDh L-DOPA
  • vehicle/pridopidine would be given 60 min (study 1) or 120 min (study 2) prior to vehicle/L-DOPA, relative to one another and to start of behavioral observations.
  • the effects of treatments on parkinsonian disability, dyskinesia, duration and quality of anti-parkinsonian benefit (on-time) and activity were assessed and analyzed for a period of 6 hours (h).
  • Dyskinesia representative of the maximum of either chorea or dystonia was scored as 0—absent, 1—mild, 2—moderate, 3—marked or 4—severe.
  • Parkinsonian disability and dyskinesia were assessed for 5-min every 10-min, the score given being most representative of each 5-min observation period. Scores were summed for each hour for time-course analyses and across the entire observation period (0-6 h). Thus, for measures parkinsonian disability and dyskinesia, the maximum scores possible (equating to severe) over the 0-6 h period were 360 and 144 respectively.
  • the duration of anti-parkinsonian action, on-time was defined as the number of minutes for which the bradykinesia score was zero.
  • the duration of on-time associated with dyskinesia of varying severity was calculated as follows. On-time with disabling dyskinesia, ‘bad’-on-time was calculated the number of minutes for which the bradykinesia score was zero while the dyskinesia score was greater than 2. Meanwhile, on-time without disabling dyskinesia, ‘good’-on-time represents the number of minutes for which the bradykinesia score is zero while the dyskinesia score is 2 or less.
  • Pridopidine binding was evaluated in radioligand binding assays as described in the materials and methods. In-vitro binding assays were performed against novel receptors and as validation of previously reported targets for pridopidine. Pridopidine was found to have highest affinity for the S1R with an IC50 of 0.14 ⁇ M (140 nM).
  • Pridopidine also shows low-affinity binding to additional receptors, in the micromolar range including serotonin (or 5-hydroxytryptamine [5-HT]) 5-HT1A, 5-HT2A, and 5-HT7; adrenergic alpha-1, adrenergic alpha-2A and alpha-2C; dopamine D3; muscarinic M2; and histamine H3 (see Table 1, below). Only negligible or no binding of pridopidine against the dopamine D2 receptors (D2R) was detected. Additional targets were tested including NMDAR, 5-HT6, Tachykinin NK1, Dopamine transporter (DAT), Norepinephrine transporter (NET) and the Serotonin transporter (SERT) with no observed binding.
  • serotonin or 5-hydroxytryptamine [5-HT]
  • 5-HT1A 5-HT1A
  • 5-HT2A 5-HT2A
  • 5-HT7 adrenergic alpha-1, adren
  • pridopidine 7, 15, 20 and 30 mg/kg All doses of pridopidine assessed (7, 15, 20 and 30 mg/kg) were well tolerated. Oral administration of pridopidine 7, 15, 20 and 30 mg/kg, was associated with geometric mean Cmax values of 384, 952, 1487 and 2676 ng/ml (corresponding to 1.4, 3.4, 5.3 and 9.5 M, respectively) and AUC 0-24 values of 1214, 4905, 8207 and 22987 ng*h/ml (corresponding to 4.3, 17.5, 29.2 and 81.8 h* ⁇ M)
  • S1R and moderate affinity receptor occupancies were assessed as indicated in Table 2, below, using (i) known binding affinities of pridopidine to human and rodent receptors in vitro (ii) published in vivo PET imaging in rats (Sahlholm 2015) and non-human primate (NHP), and (iii) the extensive pharmacokinetic profiling of pridopidine in the different species.
  • NHP data is most relevant to the following discussion.
  • Cmax values for rat and NHP as a function of oral pridopidine dose are based on internally accumulated PK data (supplementary) in addition to data presented here.
  • Rat ⁇ 1R and D2R occupancy data are based on in vivo measurements at 3 and 15 mg/kg (Sahlholm 2015),
  • NHP D2R occupancy data is based on in vivo PET imaging with the specific D2R ligand 11C-raclopride.
  • NHP ⁇ 1R occupancy data are extrapolated from in vitro binding investigations with 3H-fluspidine, known and specific ⁇ 1R tracer, against human ⁇ 1R.
  • pridopidine's effect is mainly mediated by the SIR, while at the higher dose (30 mg/kg and 20 mg/kg (study 2), pridopidine binds the S1R as well as a more complex activity of pridopidine is initiated by binding to the additional low affinity receptors.
  • pridopidine Orally administered pridopidine was well tolerated at all doses assessed.
  • the effects of acute combination of pridopidine with LDh on parkinsonian disability, dyskinesia (including dystonic and choreiform), and duration and quality of on-time are shown in FIGS. 5-10 .
  • Table 3 shows the 6 hour data presented in FIG. 5A for Dyskinesia (time course) in study 2. Pridopidine reduces established dyskinesia evoked by high L-DOPA.
  • FIG. 6A time course (0-6 hr) and FIG. 6B bar graph (0-2 hour accumulated) show levels of Parkinsonian disability. Pridopidine did not reduce the anti-parkinsonian benefit of L-DOPA (study 2).
  • Table 4 shows that there were no significant changes in parkinsonism in L-DOPA treated animals, resulting from additional therapy with pridopidine at all doses, as shown in FIG. 6A (study 2).
  • FIG. 7A-B Data from study 1: Pridopidine produced a significant and dose dependent reduction in dyskinesia evoked by L-DOPA in study 1 ( FIG. 7A-B ).
  • FIG. 7A examining the whole 6 hr time course and FIG. 7B bar graph showing individual animals at 0-2 hours accumulated after L-DOPA administration. This decrease was observed in the absence of any change to the total duration of on-time or extent of anti-parkinsonian benefit of L-DOPA.
  • the lower-dose of pridopidine (7 mg/kg) did produce a modest decrease in the anti-parkinsonian benefit afforded by L-DOPA during the first two hours of observation (from study 1, data not shown).
  • FIG. 8A-B is a bar graph showing individual animals at 0-2 hours after L-DOPA.
  • A describes data in response to vehicle-vehicle treatment).
  • Pridopidine produced a significant and dose-dependent reduction in levels of L-DOPA-induced dystonia evoked by LDh.
  • FIG. 9C shows cumulated dystonia levels at 0-2 hours post L-DOPA administration and a significant and dose-dependent reduction of L-DOPA-induced dystonia levels over a 0-2 hr time period with pridopidine.
  • FIG. 9D shows cumulated chorea levels at 0-2 hours post L-DOPA administration and a significant and dose-dependent reduction of L-DOPA-induced chorea levels over a 0-2 hr time period with pridopidine.
  • pridopidine did not negatively impact on the duration of anti-parkinsonian benefit of L-DOPA but rather altered the associated quality thereof in terms of the proportion that was either ‘good’ or ‘bad’ (on-time associated with non-disabling or disabling dyskinesia respectively).
  • the cynomolgus macaques employed in this study were rendered parkinsonian with MPTP.
  • the extent of lesion produced by this regimen (Johnston 2013) is comparable to that observed in advanced Parkinson's patients and typical of MPTP-lesioned animals with robust parkinsonism.
  • the doses of L-DOPA employed as part of the current study provided maximal anti-parkinsonian benefit, typically with a duration of ⁇ 3 h but this was compromised by disabling dyskinesia induced by L-DOPA (greater than moderate levels). Indeed, the duration of L-DOPA efficacy was mirrored by the duration of L-DOPA-induced dyskinesia.
  • the cellular target of pridopidine was evaluated in various in vitro binding assays.
  • Pridopidine binds with highest affinity to the Sigma-1 receptor (SIR, binding IC50 ⁇ 100 nM), approximately 100 fold higher affinity compared to an earlier described target, the Dopamine D2R (IC50 ⁇ 10 ⁇ M) and to several other central nervous system (CNS) receptor targets, including, serotonin (5-hydroxytryptamine [5-HT]) 5-HT1A, 5-HT2A, and 5-HT7; adrenergic alpha-1, adrenergic alpha-2A and alpha-2C; dopamine D3; and muscarinic M2, all in the mid micromolar range.
  • SIR Sigma-1 receptor
  • IC50 ⁇ 100 nM the Dopamine D2R
  • CNS central nervous system
  • pridopidine 7, 15, 20 and 30 mg/kg All doses of pridopidine assessed (7, 15, 20 and 30 mg/kg) were well tolerated. Oral administration of pridopidine 7, 15, 20 and 30 mg/kg, was associated with geometric mean C max values of 384, 952, 1487 and 2676 ng/ml (corresponding to 1.4, 3.4, 5.3 and 9.5 ⁇ M, respectively) and AUC 0-24 values of 1214, 4905, 8207 and 22987 ng*h/ml (corresponding to 4.3, 17.5, 29.2 and 81.8 h* ⁇ M) Receptor occupancy was estimated using (i) known binding affinities of pridopidine to human and rodent SIR and D2R in vitro (ii) in vivo PET imaging in rats, NHP and human, and (iii) pharmacokinetic PK profiling in the different species.
  • Example 4 Therapy for Treating LID in PD Patients
  • Periodically orally administering of pridopidine (greater than 100 mg/day, for example 105 mg/day, 110 mg/day, 135 mg/day, 150 mg/day, 175 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day) as an add-on therapy for a human subject afflicted with LID who is already receiving levodopa provides a clinically meaningful advantage in reducing the symptoms of LID.
  • pridopidine greater than 100 mg/day, for example 105 mg/day, 110 mg/day, 135 mg/day, 150 mg/day, 175 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day
  • the therapy is effective in improving symptoms of dyskinesia.
  • the therapy does not produce any significant side effects such as sedation and depression.
  • the therapy improves the bad quality on-time evoked by levodopa.
  • Periodically orally administering of pridopidine 45 mg/day, 90 mg/day, 135 mg/day or 180 mg/day
  • pridopidine 45 mg/day, 90 mg/day, 135 mg/day or 180 mg/day
  • LID who is already receiving amantadine
  • the add-on therapies also provide efficacy (provides at least an additive effect or more than an additive effect) in treating the patient without undue adverse side effects or affecting the safety of the treatment:
  • the add-on therapy is effective (provides at least an additive effect or more than an additive effect) in improving symptoms of dyskinesia.
  • the add-on therapy does not produce any significant side effects such as sedation and depression.
  • Periodically orally administering of pridopidine (45 mg/day, 90 mg/day, 135 mg/day or 180 mg/day) as an add-on therapy for a human subject afflicted with a DIMD who is already receiving or has received at least one of antidepressant, an antipsychotic, an antiepileptic, an antimicrobial, an antiarrhythmic, a mood stabilizer, a gastrointestinal drug provides a clinically meaningful advantage in treating the patient.
  • the therapy is effective (provides at least an additive effect or more than an additive effect) in improving some or all of the symptoms of DIMD.
  • the therapy does not produce any significant side effects such as sedation and depression.
  • In vivo ⁇ 1 R and D 2 R occupancies were calculated using (i) known binding-affinities of pridopidine to human in-vitro; (ii) in vivo positron-emission tomography imaging in humans and (iii) the extensive PK profiling of pridopidine in the different species.
  • Human Cmax and AUC values for 45 and 90 mg BID are from Pride-HD (Study TV7820-CNS-20002) and simulated for 150 mg BID. Human ⁇ 1R and D 2 R occupancy at 45 mg BID derived from human PET study TV7820-IMG-10082 and estimated for higher doses. a Simulated data using the population pharmacokinetic modelling
  • pridopidine to reduce PD-LID possibly involves a complex pharmacological profile, associated with high ⁇ 1 R occupancy together with multiple non-sigma receptors, including adrenergic ⁇ 2C, 5-HT 1A , and DA receptors.
  • Example 8 Treatment of Levodopa-Induced Dyskinesia (LID) in Patients with Parkinson's Disease (PD)
  • LID Levodopa-Induced Dyskinesia
  • Primary endpoint will be assessed for both the 100 mg bid and the 150 mg bid pridopidine dosages vs placebo in a hierarchical manner.
  • the primary endpoint is the mean change from Baseline (Visit 2) to Visit 7/ET in the sum of Parts 1, 3, and 4 of the Unified Dyskinesia Rating Scale (UDysRS) dose dyskinesia.
  • UDMRS Unified Dyskinesia Rating Scale

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