WO2020110128A1 - Combination of pridopidine and an additional therapeutic agent for treating drug induced dyskinesia - Google Patents

Combination of pridopidine and an additional therapeutic agent for treating drug induced dyskinesia Download PDF

Info

Publication number
WO2020110128A1
WO2020110128A1 PCT/IL2019/051313 IL2019051313W WO2020110128A1 WO 2020110128 A1 WO2020110128 A1 WO 2020110128A1 IL 2019051313 W IL2019051313 W IL 2019051313W WO 2020110128 A1 WO2020110128 A1 WO 2020110128A1
Authority
WO
WIPO (PCT)
Prior art keywords
pridopidine
additional therapeutic
therapeutic agent
effective amount
pharmaceutically effective
Prior art date
Application number
PCT/IL2019/051313
Other languages
French (fr)
Inventor
Michael Hayden
Michal Geva
Original Assignee
Prilenia Neurotherapeutics Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Prilenia Neurotherapeutics Ltd. filed Critical Prilenia Neurotherapeutics Ltd.
Publication of WO2020110128A1 publication Critical patent/WO2020110128A1/en
Priority to US17/315,667 priority Critical patent/US12036213B2/en

Links

Classifications

    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/49—Cinchonan derivatives, e.g. quinine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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

Definitions

  • This invention is directed to a method of treating a subject afflicted with a drug-induced movement disorder including levodopa-induced dyskinesia comprising periodically administering to the subject in need thereof an amount of pridopidine in combination with an additional therapeutic agent effective to treat the subject.
  • the major groups of drugs responsible for DIMDs include antidepressants, antipsychotics, antiepileptics, antimicrobials, antiarrhythmics, mood stabilizers and gastrointestinal drugs, among others. These movement disorders include, without limitation, parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics.
  • Parkinson Parkinson’s disease and Levodopa-induced dyskinesia
  • Dyskinesias are common in Parkin on’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).
  • Parkinson’s disease patients is associated with the development of dyskinesias with chronic use.
  • Dyskinesia is a major complication of dopamine -replacement therapy in PD (“PD-LID”; Kumar 2005, Manson 2012, Poewe 2009).
  • 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 1 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.
  • L-DOPA-induced dyskinesia LID
  • AMT amantadine
  • Pridopidine (formerly ACR16, Huntexil®) is a drug in development for the treatment of patients with Huntington disease.
  • the chemical name of pridopidine base is 4-(3- (methylsulfonyl)phenyl)-l-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 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, (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.
  • ER endoplasmic reticulum
  • transcriptomic analysis of rat striatum showed that pridopidine treatment activates expression of the brain- derived neurotrophic factor (BDNF), dopamine receptor 1 (DIR), glucocorticoid receptor (GR), and the serine-threonine kinase protein kinase B (Akt)/phosphoinositide 3 -kinase (PI3K) pathways, known to promote neuronal plasticity and survival and to be impaired in HD.
  • BDNF brain- derived neurotrophic factor
  • DIR dopamine receptor 1
  • GR glucocorticoid receptor
  • Akt serine-threonine kinase protein kinase B
  • PI3K serine-threonine kinase protein
  • the present invention provides a method of treating drug-induced movement disorder (DIMD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent.
  • DIMD drug-induced movement disorder
  • the present invention provides a method of treating levodopa-induced dyskinesia (LID) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent.
  • the subject is afflicted with Parkinson’s disease.
  • the subject is afflicted with parkinsonism other than Parkinson’s disease.
  • the present invention further provides a method of alleviating or reducing a symptom associated with the levodopa treatment in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent.
  • the symptom is abnormal movements, myoclonic jerks, irregular movements of extremities, gait, facial grimacing, ataxia, inability to sustain motor act, hand movement or balance, choreiform peak dose dyskinesia, or dystonic peak dose dyskinesia.
  • the symptom is bad quality on-time evoked by levodopa.
  • the one or more additional therapeutic agent is selected from the group consisting of Amantadine, Dipraglurant (ADX48621), Foliglurax, IRF790, Eltoprazine, Buspirone, Fevetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof.
  • Figures 1-3 show the effect of pridopidine in historic studies of Huntington disease.
  • Figures 1A and IB Graphs showing the effect of 45 mg bid pridopidine on Total Motor Score (TMS), full analysis set from MermaiHD ( Figure 1A) and HART (Figure IB) studies, respectively. In both graphs, the upper line shows results with placebo treatment, the lower line shows results with 45 mg bid treatment.
  • 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).
  • Figure 4 Reproduction of a PET scan showing levels of S IR occupancy by pridopidine in the brain of healthy volunteers before (upper panel) and after (lower panel) a single dose of 45 mg pridopidine.
  • Figures 5-10 show the effect of pridopidine in combination with a high F-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 F-DOPA induced dyskinesia, including choreiform and dystonic dyskinesia evoked by high-dose L-DOPA without affecting the beneficial anti-parkinsonian effects of L-DOPA.
  • Figure 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.
  • Figure 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.
  • Figure 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.
  • Figure 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.
  • Figure 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.
  • Figure 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.
  • Figure 9A Graph showing that pridopidine reduces L-DOPA induced dystonia (0-6 hours accumulated, study 1). Pridopidine reduces established dystonia evoked by high dose L-DOPA. Y axis is severity of dystonia, X axis shows pridopidine doses.
  • Figure 9B 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.
  • Figure 10 Bar graph showing the effects of pridopidine on duration and quality of on-time (study 2).
  • Figures 11A-11D present change in levels of AIMs following treatment with pridopidine at different doses, as described in Example 8.
  • the AIMs level was measured. Most significant results were obtained with 30 and 60 mg/kg.
  • Figure 11A presents change in levels of AIMs over 3 hours measured every 20 minutes at different doses of pridopidine 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg vs. vehicle.
  • Figure 11B presents a total of 20-120 min totals bars of results presented in Figure 11 A.
  • Figure 11C presents net contraversive rotations of the rats during 3 hours measured every 20 minutes at different doses of pridopidine 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg vs. vehicle.
  • Figure 11D presents a 20-120 min total bars of results presented in Figure 11C. P-values are presented in the corresponding tables.
  • Figures 12A-12C present AIMs subscores (time-courses) per 20 minutes of Fimb, Axial and Orolingual following treatment with pridopidine at different doses as described in Example 7.
  • Figure 12A presents the Fimb AIMs results.
  • Figure 12B presents the Axial AIMs results.
  • Figure 12C presents the Orolingual AIMs results.
  • Figures 13A-13C are bar graphs presentations of the time course shown in Figure 12, total of 20- 120 min of AIMs subscores (20-120 min totals) bars (Fimb, Axial and Orolingual) following treatment with pridopidine at different doses as presented in Figures 12A to 12C and described in Example 8.
  • Figure 13A presents the Fimb results.
  • Figure 13B presents the Axial results.
  • Figure 13C presents the Orolingual results.
  • Figures 14A-14D present change in levels of AIMs following treatment with sub optimal dose pridopidine (15 mg/kg) with 5 mg/kg and 10 mg/kg amantadine (AMT), as described in Example 7.
  • Figure 14A presents change in levels of AIMs during 3 hours measured every 20 minutes.
  • Figure 14B presents a total of 20-120 min total bars of results presented in Figure 14A.
  • Figure 14C presents net contraversive rotations of the rats over 3 hours measured every 20 minutes.
  • Figure 14D presents a 20-120 min total bars of results presented in Figure 14C.
  • the present invention provides a method of treating drug-induced movement disorder (DIMD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent.
  • DIMD drug-induced movement disorder
  • the one or more additional therapeutic agent is in its neutral form or in its salt form, such as a pharmaceutically acceptable salt.
  • the one or more additional therapeutic agent is administered as an add on therapy. In one embodiment, the one or more additional therapeutic agent is administered in combination with pridopidine. In another embodiment, pridopidine and the additional therapeutic agent are co-formulated. In another embodiment, the pridopidine and the additional therapeutic agent are separated pharmaceutical formulations.
  • 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 is selected from parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics.
  • the DIMD is Tardive dyskinesia or drug-induced dystonia.
  • the DIMD comprises dyskinesia.
  • the dyskinesia is levodopa-induced dyskinesia (LID).
  • the subject is afflicted with Parkinson’s disease. In one embodiment, the subject is afflicted with parkinsonism other than Parkinson’s disease.
  • the subject is concurrently being treated with levodopa.
  • the pridopidine and the one or more additional therapeutic agent are administered simultaneously with the levodopa.
  • the pridopidine and the one or more additional therapeutic agent are administered after the levodopa is administered for a period of time.
  • the levodopa is administered after the pridopidine and the one or more additional therapeutic agents are administered for a period of time.
  • the period of time is from 10 min to 18 hours, for example, 10 min, 15 min, 20 min, 25 min, 30 min, 45 min, 1.0 hour, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours, 5.0 hours, 6.0 hours, 7.0 hours, 8.0 hours, 9.0 hours, 10.0 hours, 11.0 hours, 12.0 hours, 15 hours or 18 hours.
  • the period of time is 10 min, 20 min, 30 min, 45 min, 1.0 hour, 2.0 hours, 6.0 hours, or 12 hours.
  • the period of time is from 10 min to 1 hour.
  • the period of time is from 10 min to 3 hours.
  • the period of time is from 1 hour to 3 hours.
  • the period of time is from 2 hours to 5 hours. In another embodiment, the period of time is from 4 hours to 10 hours. In another embodiment, the period of time is from 6 hours to 12 hours. In another embodiment, the period of time is from 12 hours to 18 hours.
  • the method of the invention further alleviates or reduces a symptom associated with the levodopa treatment in a subject in need thereof.
  • the symptom is abnormal movements, myoclonic jerks, irregular movements of extremities, gait, facial grimacing, ataxia, inability to sustain motor act, hand movement or balance, choreiform peak dose dyskinesia, or dystonic peak dose dyskinesia.
  • the symptom is bad quality on-time evoked by levodopa.
  • the administration of the pridopidine and the one or more additional therapeutic agent improves the symptom of the levodopa induced dyskinesia by at least 10%, by at least 20%, by at least 30% or by at least 50% as measured by AIMS, Rush Dyskinesia Rating Scale (RDRS), MDS-UPDRS or UDysRS.
  • AIMS Rush Dyskinesia Rating Scale
  • RDRS Rush Dyskinesia Rating Scale
  • MDS-UPDRS MDS-UPDRS
  • UDysRS UDysRS
  • the pridopidine and the one or more additional therapeutic agent are administered simultaneously or sequentially. In one embodiment, pridopidine and the one or more additional therapeutic agents are administered once daily, twice daily, three times daily, or four times daily. In one embodiment, pridopidine and the one or more additional therapeutic agents are administered less than once daily. In one embodiment, pridopidine and the one or more additional therapeutic agents are administered every other day. In one embodiment, pridopidine and the one or more additional therapeutic agents are administered once weekly or bi-weekly.
  • the pridopidine is in the form of a pridopidine salt.
  • the pridopidine salt is pridopidine hydrochloride.
  • the pridopidine is the hydrobromide, the L-tartrate, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate or the toluene-p- s
  • the pridopidine which is administered with one or more additional therapeutic agent is administered at a dose of from 10 mg to 500 mg, for example, 10 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 67.5 mg, 75 mg, 100 mg, 112.5 mg, 125 mg, 135 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg.
  • the pridopidine is administered at a dose of from 10 mg to 100 mg.
  • the pridopidine is administered at a dose of from 10 mg to 20 mg. In one embodiment, the pridopidine is administered at a dose of from 10 mg to 50 mg. In one embodiment, the pridopidine is administered at a dose of from 20 mg to 80 mg. In one embodiment, the pridopidine is administered at a dose of from 10 mg to 150 mg. In one embodiment, the pridopidine is administered at a dose of from 45 mg to 150 mg. In one embodiment, the pridopidine is administered at a dose of from 10 mg to 200 mg. In one embodiment, the pridopidine is administered at a dose of from 100 mg to 300 mg. In one embodiment, the pridopidine is administered at a dose indicated above once daily, twice daily, three times daily, or four times daily.
  • the pridopidine is administered at a dose of 100 mg once daily, twice daily, or three times daily. In one embodiment, the pridopidine is administered at a dose of 112.5 mg once daily, twice daily, three times daily, or four times daily. In one embodiment, the pridopidine is administered at a dose of 120 mg once daily, twice daily, or three times daily. In one embodiment, the pridopidine is administered at a dose of 150 mg once daily, twice daily, or three times daily. In one embodiment, the pridopidine is administered at a dose of 175 mg once daily, twice daily, three times daily, or four times daily.
  • the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Amantadine.
  • the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Amantadine.
  • the one or more additional therapeutic agent comprises Amantadine at a dose of between 10-400 mg, for example, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350, 375 mg, or 400 mg.
  • the dose of Amantadine is 10, 50, 100, 137, 150, 200, 250, 274, 300, 350, or 400 mg.
  • the one or more additional therapeutic agent comprises Amantadine at a dose of between 10-100 mg.
  • the one or more additional therapeutic agent comprises Amantadine at a dose of between 50-150 mg.
  • the one or more additional therapeutic agent comprises Amantadine at a dose of between 100-250 mg.
  • the one or more additional therapeutic agent comprises Amantadine at a dose of between 200-400 mg.
  • the Amantadine is administered once daily, twice daily, three times daily, or four times daily.
  • the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Dipraglurant.
  • the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agents comprise Dipraglurant.
  • the one or more additional therapeutic agents comprise Dipraglurant at a dose of 10-400 mg, for example, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350, 375 mg, or 400 mg.
  • the amount of Dipraglurant is 50, 100, 200, 250, or 300 mg.
  • the one or more additional therapeutic agent comprises Dipraglurant at a dose of between 10-100 mg.
  • the one or more additional therapeutic agent comprises Dipraglurant at a dose of between 50-150 mg.
  • the one or more additional therapeutic agent comprises Dipraglurant at a dose of between 100-250 mg.
  • the one or more additional therapeutic agent comprises Dipraglurant at a dose of between 200-400 mg.
  • Dipraglurant is administered once daily, twice daily, three times daily, or four times daily.
  • the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Foliglurax.
  • the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Foliglurax.
  • the one or more additional therapeutic agent comprises Foliglurax in a dose of between 10-50 mg, for example, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.
  • the amount of Foliglurax is 10 mg, 20 mg, 30 mg, or 40 mg.
  • the Dipraglurant is administered once daily, twice daily, three times daily, or four times daily.
  • the one or more additional therapeutic agent comprises IRL790 in a dose of between of 1-50 mg. In another embodiment, the one or more additional therapeutic agent comprises IRL790 in a dose of between of 50-100 mg. In another embodiment, the one or more additional therapeutic agent comprises IRL790 in a dose of between of 75-150 mg. In one embodiment, the IRL790 is administered once daily, twice daily, three times daily, or four times daily.
  • the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Buspirone.
  • the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Buspirone.
  • the one or more additional therapeutic agent comprises Buspirone in an amount of 1-50 mg, for example, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, or 50 mg.
  • the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Levetiracetam.
  • the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Levetiracetam.
  • the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 100-2000 mg.
  • the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 500-1000 mg. In one embodiment, the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 750-1500 mg. In one embodiment, the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 750-2000 mg. In one embodiment, the Levetiracetam is administered once daily, twice daily, three times daily, or four times daily.
  • the weight ratio between the pridopidine and the one or more additional therapeutic agent is from about 1:20 to about 20: 1. In one embodiment, the weight ratio between the pridopidine and the one or more additional therapeutic agent is about 1:20, about 1: 15, about 1:10, about 1:7.5, about 1:5.0, about 1:2.5, about 1:1, about 2.5:1, about 5:1, about 7.5: 1, about 10:1, about 15: 1 or about 20:1.
  • Dipraglurant as used herein, has been studied in trials for the treatment of Parkinson's Disease, which has a chemical name of 6-fluoro-2-(4-pyridin-2-ylbut-3-ynyl)imidazo[l,2- a] pyridine.
  • Dipraglurant as used herein refers to Dipraglurant base or any pharmaceutically acceptable salt thereof
  • IRF790 is an experimental small molecule compound with psychomotor stabilizing properties and potently reduced levodopa-induced involuntary movement without impairing the antiparkinsonian effect of levodopa.
  • IRF790 as used herein refers to IRF790 base or any pharmaceutically acceptable salt thereof
  • Eltoprazine as used herein, has been used in trials studying the treatment of schizophrenia and cognitive impairment, which has a chemical name of l-(2,3-dihydro-l,4-benzodioxin-5- yl)piperazine.
  • Eltoprazine as used herein refers to Eltoprazine base or any pharmaceutically acceptable salt thereof.
  • Buspirone is an anxiolytic agent, which has a chemical name of 8-[4-(4- pyrimidin-2-ylpiperazin-l-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione.
  • Buspirone as used herein refers to Buspirone base or any pharmaceutically acceptable salt thereof
  • Levetiracetam as used herein, has antiepileptic activity. Its chemical name is (2S)-2-(2- oxopyrrolidin-l-yl)butanamide. Levetiracetam as used herein refers to Levetiracetam base or any pharmaceutically acceptable salt thereof
  • Nuedexta (dextromethorphan/Quinidine), as used herein, is a central nervous system agent for the treatment of PseudoBulbar Affect (PBA), a medical condition that causes involuntary, sudden, and frequent episodes of crying and/or laughing in people living with certain neurologic conditions or brain injury.
  • PBA PseudoBulbar Affect
  • Nuedexta refers to Nuedexta base or any pharmaceutically acceptable salt thereof.
  • the present invention further provides a method of treating LID in a subject with PD comprising administering to the subject an amount of pridopidine and one or more additional therapeutic agent 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 and one or more additional therapeutic agent 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 and one or more additional therapeutic agent effective to treat the dyskinesia in the subject.
  • a drug other than levodopa for example an anti-depressant or an anti-psychotic
  • administering comprising administering to the subject an amount of pridopidine and one or more additional therapeutic agent 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 and one or more additional therapeutic agent effective to treat the DIMD.
  • the invention also provides pridopidine and one or more additional therapeutic agent 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 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 and one or more additional therapeutic agent effective to treat the subject.
  • the invention provides pridopidine and one or more additional therapeutic agent 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 and one or more additional therapeutic agent, wherein the amounts when taken together are effective to treat the human subject.
  • pridopidine and one or more additional therapeutic agent 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 amount of pridopidine is between 10 mg/day up to 500 mg/day.
  • the amount of pridopidine is 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 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, 400 mg/day or 500 mg/day.
  • the AUCO-inf 24 achieved is 500 h*ng/ml to 60,000 h*ng/ml or 1,000 h*ng/ml to 5,000 h*ng/ml or 3,000 h*ng/ml to 10,000 h*ng/ml or 5,000 h*ng/ml to 12,000 h*ng/ml or 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/ml.
  • 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; (c) one or more additional therapeutic agent and a pharmaceutically acceptable carrier.
  • the package also comprises (c) instructions for use of the first, second and additional therapeutic agent 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 HC1.
  • This invention additionally provides use of an amount of levodopa and an amount of pridopidine and an amount of an additional therapeutic agent 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 and the one or more therapeutic agent 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 and one or more therapeutic agent by periodically administering the pharmaceutical composition, the pridopidine and the one or more additional therapeutic agent to the subject.
  • This invention also provides a pharmaceutical composition comprising an amount of pridopidine and one or more additional therapeutic agent for use treating a subject afflicted with levodopa induced dyskinesia as an add-on therapy or in combination with levodopa and/or additional therapeutic agent by periodically administering the pharmaceutical composition to the subject.
  • the methods of this invention make use of a composition comprising pridopidine or salt thereof in combination with one or more additional therapeutic agent.
  • the composition comprising pridopidine or salt thereof further comprises at least one analog of pridopidine selected from the following structures of compounds 1-7:
  • composition comprising pridopidine or salt thereof further comprises at least an analog of compound (1); or at least an analog of compound (4); or comprising analogs of compound (1) and of compound (4).
  • 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 Rush Dyskinesia Rating Scale (RDRS), the Unified Dyskinesia Rating Scale (UdysRS) or AIMS rating scale (Goetz 2008b, Ecdeu 1976, the entire contents of which are hereby incorporated by reference).
  • RDRS Rush Dyskinesia Rating Scale
  • UdysRS Unified Dyskinesia Rating Scale
  • AIMS rating scale Goetz 2008b, Ecdeu 1976, the entire contents of which are hereby incorporated by reference.
  • 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 and one or more additional therapeutic agent 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 or salt thereof and one or more additional therapeutic agent 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 or salt thereof and one or more additional therapeudc agent 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 one or more additional therapeutic agent 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, the one or more additional therapeutic agent and the levodopa are co-formulated. In another embodiment, the amount of pridopidine, the amount of one or more additional therapeutic agent are co-formulated. In another embodiment, the amount of pridopidine, the one or more additional therapeutic agent 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 and the one or more additional therapeutic agent 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, Rush Dyskinesia Rating Scale (RDRS), 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 DIMD is myoclonus.
  • the DIMD is tics.
  • the pridopidine and the one or more therapeutic agent are administered via oral administration. In another embodiment, the pridopidine and the one or more therapeutic agent are administered daily. In another embodiment, pridopidine and the one or more therapeutic agent are administered twice daily. In some embodiments one-unit dose of the pridopidine is administered within 60 minutes of awakening and a second dose is administered after 6-10 hours. In another embodiment, pridopidine and the one or more therapeutic agent is administered thrice daily. In another embodiment, the pridopidine is a pridopidine salt. In another embodiment, the pridopidine salt is provided as pridopidine hydrochloride (pridopidine HC1).
  • the amount of pridopidine (administered in combination with one or more additional therapeutic agent to a subject in need thereof) is between 10-500 mg/day. In another embodiment, the amount of pridopidine is 10 mg/day. 15 mg/day, 20 mg/day, 22.5 mg/day, 45 mg/day, 67.5 mg/day, 75 mg/day, 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 , 400 mg/day or 500 mg/day.
  • the amount of pridopidine administered is from above 10 mg per day to 100 mg per day. In another embodiment, the amount of pridopidine administered is from above 10 mg per day to 200 mg per day. In another embodiment, the amount of pridopidine administered is from above 100 mg per day to 300 mg per day. In another embodiment, the amount of pridopidine administered is from above 100 mg per day to 400 mg per day. In another embodiment, the amount of pridopidine administered is from above 200 mg per day to 350 mg per day. In another embodiment, the amount of pridopidine administered is from above 100 mg per day to 350 mg per day. In another embodiment, the amount of pridopidine administered is more than 100 mg per day to 400 mg per day.
  • 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 tid (thrice daily), 90 mg tid, 100 mg tid, or 125 mg tid. In another embodiment, 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 HC1, twice daily.
  • pridopidine administered in combination with one or more additional therapeutic agent
  • pridopidine is administered at a daily dose of between 10 mg to 500 mg given in the form of pridopidine HC1.
  • pridopidine is administered at a daily dose of 10 mg, 20 mg, 45mg, 90 mg, 135 mg, 180 mg, 225 mg, 300 mg, 350 mg, 400 mg or 500 mg given in the form of pridopidine HC1.
  • the specified dosage of pridopidine is administered in two equal doses.
  • pridopidine is administered to a subject in need thereof in an amount to achieve an AUC0-24 plasma level of between 500 h*ng/ml to about 60,000 h*ng/ml; 1,000 h*ng/ml to 5,000 h*ng/ml, 3,000 h*ng/ml to 10,000 h*ng/ml, 5,000 h*ng/ml to 12,000 h*ng/ml, 12,000 h*ng/ml to 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, 15,000 h*ng/ml to 45,000 h*ng/ml, 15,000 h*ng/ml, 15,000 h*ng/
  • the method further comprises administering to the subject a therapeutically effective amount of levodopa.
  • the amount of pridopidine administered to the subject is 10 mg/day, 20 mg/day, 22.5 mg/day, 45 mg/day, 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, 400 mg/day or 500 mg/day.
  • pridopidine is administered at a daily dose of between 10 mg-500 mg given in the form of pridopidine HC1.
  • pridopidine is administered at a daily dose of 10 mg, 15 mg, 22.5 mg, 45 mg, or 90 mg, 135 mg, 180 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg or 500 mg given in the form of pridopidine HC1.
  • 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 one or more additional therapeutic agent which is selected from the group consisting of Amantadine, Dipraglurant (ADX48621), Foliglurax, IRL790, Eltoprazine, Buspirone, Levetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof.
  • a one or more additional therapeutic agent which is selected from the group consisting of Amantadine, Dipraglurant (ADX48621), Foliglurax, IRL790, Eltoprazine, Buspirone, Levetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof.
  • 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 an additional therapeutic agent are administered simultaneously.
  • the administration of the additional therapeutic agent substantially precedes the administration of pridopidine.
  • the administration of pridopidine substantially precedes the administration of the additional therapeutic agent.
  • the subject is receiving an additional therapeutic agent 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 an additional therapeutic agent therapy or levodopa therapy. In another embodiment, 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.
  • the pridopidine is administered adjunctively to the additional therapeutic agent.
  • the additional therapeutic agent 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.
  • 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 and the amount of the one or more additional therapeutic agent, 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 and one or more additional therapeutic agent improves a symptom of the levodopa induced dyskinesia by at least 4%. In an embodiment of the present invention, the administration of levodopa and pridopidine and one or more additional therapeutic agent, improves a symptom of the levodopa induced dyskinesia by at least 5% In an embodiment of the present invention, the administration of levodopa and pridopidine and one or more additional therapeutic agent, improves a symptom of the levodopa induced dyskinesia by at least 10%.
  • the administration of levodopa and pridopidine and one or more additional therapeutic agent improves a symptom of the levodopa induced dyskinesia by at least 20%.
  • the administration of levodopa and pridopidine and one or more additional therapeutic agent improves a symptom of the levodopa induced dyskinesia by at least 30%.
  • the administration of levodopa and pridopidine and one or more additional therapeutic agent improves a symptom of the levodopa induced dyskinesia by at least 50%.
  • the administration of levodopa and pridopidine and one or more additional therapeutic agent improves a symptom of the levodopa induced dyskinesia by more than 100%. In another embodiment, the administration of levodopa and pridopidine and one or more additional therapeutic agent, 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 one or more additional therapeutic agent 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 one or more therapeutic agent is administered orally.
  • the one or more therapeutic agent is administered through a nasal, inhalation, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route.
  • the one or more therapeutic agent is administered daily.
  • the one or more therapeutic agent is administered more often than once daily.
  • the administration of the one or more therapeutic agent is effected twice a day.
  • the one or more therapeutic agent is administered less often than once daily.
  • the amount of pridopidine administered is 180-400 mg/day. In another embodiment, the amount of pridopidine administered is 200-500 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. In another embodiment, the amount of pridopidine administered is 500 mg/day.
  • the method further comprises administration of a one or more therapeutic agent which is an antidepressant, a psychotropic drug, an antipsychotic, amisulpride, haloperidol, olanzapine, risperidone, sulpiride, or tiapride.
  • a one or more therapeutic agent which is an antidepressant, a psychotropic drug, an antipsychotic, amisulpride, haloperidol, olanzapine, risperidone, sulpiride, or tiapride.
  • the periodic administration of the one or more additional therapeutic agent and pridopidine continues for at least 3 days.
  • the periodic administration of the one or more additional therapeutic agent and pridopidine continues for more than 30 days.
  • the periodic administration of the one or more additional therapeutic agent and pridopidine continues for more than 42 days.
  • the periodic administration of the one or more additional therapeutic agent and pridopidine continues for 8 weeks or more. In another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for at least 12 weeks. In another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for at least 24 weeks. In another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for more than 24 weeks. In yet another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for 6 months, or 12 months or more.
  • 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.
  • 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.
  • 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.
  • the specific effective amount varies with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.
  • administration of an effective amount of a therapeutic compound is 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.
  • “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 derivatives or analogs thereof, for example deuterium-enriched version of pridopidine and salts.
  • 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.
  • pridopidine is provided as a pharmaceutically acceptable salt, such as the HC1 salt or tartrate salt.
  • 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.
  • 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 HC1 to mass of pridopidine base is 0.885 (e.g. 1 mg pridopidine HC1 x 0.885 mg pridopidine base). Accordingly, 112.99 mg/day dose of pridopidine HC1 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
  • 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.
  • AUCo-t refers to the area under the plasma, serum or blood concentration versus time curve wherein t (hours) is the last measured time point.
  • AUCinfmity refers to the area under the plasma, serum or blood concentration versus time curve extrapolated to infinity.
  • AUC24 ,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 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.
  • the non-toxic inorganic and organic acid addition salts such as the hydrochloride,
  • pridopidine is provided as a pharmaceutically acceptable salt, such as the HC1 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 drage, 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. Add-On/Combination Therapy
  • 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:
  • “add-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 an additional therapeutic agent therapy to a Parkinson’s disease patient already receiving levodopa therapy 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 Prescribes’ 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.
  • the extended release formulation of amantadine is OSMOLEX® ER or GOCOVRI®
  • 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: a-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) In another embodiment, by the Rush Dyskinesia Rating Scale (RDRS).
  • UPDRS Unified Parkinson's Disease Rating Scale
  • RDRS Rush Dyskinesia 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.
  • LID Unified Dyskinesia Rating Scale
  • RDRS Rush Dyskinesia Rating Scale
  • the UDysRS having both subjective and objective dyskinesia ratings, rate all aspects of LID including features such as chorea and dystonic movements (Goetz 2013, the entire contents of which are hereby incorporated by reference).
  • 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).
  • 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 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 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), triflu
  • pridopidine refers to the quantity of pridopidine (or the quantities of pridopidine and an additional therapeutic agent) that is sufficient to yield a desired therapeutic response.
  • pridopidine and an additional therapeutic agent are administered with acetophenazine (Tindal). In some embodiments, pridopidine and an additional therapeutic agent are administered with amoxapine (Asendin). In some embodiments, pridopidine and an additional therapeutic agent are administered with chlorpromazine (Thorazine). In some embodiments, pridopidine and an additional therapeutic agent are administered with fluphenazine (Permitil, Prolixin). In some embodiments, pridopidine and an additional therapeutic agent are administered with haloperidol (Haldol).
  • pridopidine and an additional therapeutic agent are administered with loxapine (Loxitane, Daxolin). In some embodiments, pridopidine and an additional therapeutic agent are administered with mesoridazine (Serentil). In some embodiments, pridopidine and an additional therapeutic agent are administered with metaclopramide (Reglan). In some embodiments, pridopidine and an additional therapeutic agent are administered with molinndone (Lindone, Moban). In some embodiments, pridopidine and an additional therapeutic agent are administered with perphanzine (Trilafrom, Triavil). In some embodiments, pridopidine and an additional therapeutic agent are administered with piperacetazine (Quide).
  • pridopidine and an additional therapeutic agent are administered with prochlorperzine (Compazine, Combid). In some embodiments, pridopidine and an additional therapeutic agent are administered with promazine (Sparine). In some embodiments, pridopidine and an additional therapeutic agent are administered with promethazine (Phenergan). In some embodiments, pridopidine and an additional therapeutic agent are administered with thiethylperazine (Torecan). In some embodiments, pridopidine and an additional therapeutic agent are administered with thioridazine (Mellaril). In some embodiments, pridopidine and an additional therapeutic agent are administered with thiothixene (Navane).
  • pridopidine and an additional therapeutic agent are administered with trifluoperazine (Stelazine). In some embodiments, pridopidine and an additional therapeutic agent are administered with triflupromazine (Vesprin). In some embodiments, pridopidine and an additional therapeutic agent are 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).
  • Rush Dyskinesia Rating Scale developed by the Movement Disorder Society (MDS) was created to objectively assess severity of overall dyskinesia based on interference in activities of daily living, to distinguish between chorea, dystonia, and other types of dyskinesia observed and to identify the most disabling form of dyskinesia.
  • Part II (items 5-17) relates to Activities of Daily Living and refers to speech, swallowing, handwriting and the like.
  • Part III (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.
  • DIMD change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 through 7) from baseline to end of long-term therapy (Week 54) as assessed by blinded central video rating; proportion of subjects who are a treatment success at the end of long-term therapy (Week 54), based on the Clinical Global Impression of Change (CGIC) (in which a treatment success is defined as Much or Very Much Improved); change in the modified Craniocervical Dystonia (CDQ-24) score from baseline of this study to the end of long-term therapy (Week 54); proportion of subjects who have a 50% or greater reduction in AIMS score from baseline of this study to the end of long term therapy (Week 54); proportion of subjects who are a treatment success at the end of long-term therapy (Week 54), based on the Patient Global Impression of Change (PGIC) (in which a treatment success is defined as Much or Very Much Improved); percent change in AIMS score from Baseline of this study to the end of long term therapy (Week 54); and based on
  • Rating scales including UPDRS, RDRS, 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.
  • 0.1-2.5mg/day includes 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, etc. up to 2.5 mg/day.
  • 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 45mg bid pridopidine) de Yebenes 2011; Huntington Study Group HART investigators 2013; the entire contents of which are hereby incorporated by reference).
  • S IR and D2R dopamine-2 receptor
  • the study consisted of a screening period of up to 8 weeks prior to first dosing of tracer, including a T1 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.
  • 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. Results:
  • pridopidine in complex pathologies such as DIMD may be mediated by its interaction with both the S IRs and the low affinity dopamine receptors (i.e. D2R).
  • pridopidine at 45 mg bid selectively occupies the S IR 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 AUCo-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 pmole/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 AUCo- 24 levels of -12000 h*ng/ml which corresponds closely to the AUCo- 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 S IRs 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.
  • In vitro binding studies were performed at Eurofins Panlabs Taiwan, Ltd to evaluate IC50/Ki values for affinity of pridopidine to sites including s ⁇ , s2, adrenergic a2C, a2A, 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 MathlQTM (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 MathlQTM. 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.
  • the MS/MS system was an MDS Sciex API-4000 mass spectrometer with an electrospray ionization probe (Toronto, Canada). Chromatographic separation of the analytes was achieved on an Agilent Zorbax SB-C18 column. 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.
  • BLQ Limit of Quantification
  • pridopidine The pharmacokinetic profile of pridopidine was also characterized in plasma samples collected at multiple time -points up to 24h 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 S IR / D2/3R receptor occupancy.
  • Fresh fruit, primate pellets and water were available ad libitum other than at times of overnight fasting (from 5 pm) prior to days of behavioral assessment.
  • the housing rooms were subject to a 12-hour light-dark cycle (lights on 7 a.m.), 20-25 °C in a room containing only animals of the same sex.
  • 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 for at least 4-months.
  • 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 S IR with an IC50 of 0.14 mM (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]
  • nH Hill coefficient, defining the slope of the competitive binding curve, was calculated using MathlQTM.
  • 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 mM, respectively) and AUC O -24 values of 1214, 4905, 8207 and 22987 ng*h/ml (corresponding to 4.3, 17.5, 29.2 and 81.8 h*pM)
  • S 1R 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
  • 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 s 1 R 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 s 1 R occupancy data are extrapolated from in vitro binding investigations with 3H-fluspidine, known and specific s 1 R tracer, against human s 1 R.
  • pridopidine binds the SIR as well as a more complex activity of pridopidine is initiated by binding to the additional low affinity receptors.
  • 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 Figures 5-10.
  • the G I R and D2R occupancies was estimated using (i) known binding-affinities of pridopidine to human and rodent receptors in-vitro; (ii) published in-vivo PET imaging in rats and PET imaging in monkeys, and; (iii) the extensive PK profiling of pridopidine in the different species. A summary of these data is shown in Table 2A:
  • NHP D2R occupancy data is based on in vivo PET imaging with pridopidine (SC) the specific D2R ligand u C-raclopride.
  • Human D2R data is estimated based on NHP data.
  • NHP and human oiR occupancy data are extrapolated from in vitro binding investigations with 3 H-fluspidine, known and specific G I R tracer, against human G I R.
  • Table 3 shows the 6 hours data presented in Fig. 5A for Dyskinesia (time course) in study 2. Pridopidine reduces established dyskinesia evoked by high L-DOPA.
  • ns not significant. */**/*** represents P ⁇ 0.05, P ⁇ 0.01 or P ⁇ 0.001 cf. vehicle-treatment. 2-way RM ANOVA with Holm-Sidak's test or Friedman test with DUNN'S test.
  • 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).
  • Table 4 Pridopidine had no adverse effect on the anti-parkinsonian benefit of L-DOPA
  • ns not significant. */**/*** represents P ⁇ 0.05, P ⁇ 0.01 or P ⁇ 0.001 cf. vehicle-treatment. 2-way RM ANOVA with Holm-Sidak's test or Friedman test with DUNN'S test
  • 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 binds with highest affinity to the Sigma- 1 receptor (S IR, binding IC50 ⁇ lOOnM), approximately 100 fold higher affinity compared to an earlier described target, the Dopamine D2R (IC50 ⁇ 10 mM) and to several other central nervous system (CNS) receptor targets, including, serotonin (5 -hydroxy tryptamine [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.
  • S IR Sigma- 1 receptor
  • IC50 ⁇ 10 mM the Dopamine D2R
  • CNS central nervous system
  • pridopidine greater or equal to 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
  • pridopidine greater or equal to 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 provides efficacy in treating the patient without undue adverse side effects or affecting the safety of the treatment:
  • 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 does not affect the anti -parkinsonian benefit of L-DOPA.
  • pridopidine for example 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 90 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 500 mg/day
  • pridopidine for example 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 90 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 500 mg/day
  • 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.
  • pridopidine Periodically orally administering of pridopidine (for example for example 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 90 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 500 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.
  • pridopidine for example for example 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 90 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 500 mg/day
  • antidepressant for example for example 10 mg/day,
  • the therapy also provides efficacy in treating the patient without undue adverse side effects or affecting the safety of the treatment:
  • 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.
  • pridopidine for example 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 90 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day or 500 mg/day
  • additional therapeutic agent for example 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 90 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day or 500 mg/day
  • one or more additional therapeutic agent 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.
  • the additional therapeutic agent includes Amantadine, Dipraglurant (ADX48621), Foliglurax, IRL790, Eltoprazine, Buspirone, Levetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof.
  • the therapy provides efficacy in treating the patient without undue adverse side effects or affecting the safety of the treatment:
  • 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 does not affect the anti -parkinsonian benefit of L-DOPA.
  • the therapy improves the bad quality on-time evoked by levodopa.
  • the second Experiment assessed the anti-dyskinetic benefit of a single dose of pridopidine (15 mg/kg, PO) previously shown to produce subthreshold results, given alone and in combination with two suboptimal doses of AMT (5 and 10 mg/kg, SC) (Figs. 14A-14D) that were characterized previously to produce subthreshold (5 mg/kg) and an approximate 50% reduction (10 mg/kg) in AIMs and net contraversive rotations.
  • AIMs L-DOPA-induced abnormal involuntary movements
  • the power calculation was based upon defining a change in levels of AIMs during the peak-effect period (20-120 min post L-DOPA administration). This endpoint was chosen as it is potentially the most variable. A minimal effect size of 25% was defined, t chosen as it represents the smallest definable change, a 1 -point change on the basic 4-point rating that comprises the cumulative AIMs score.
  • L-DOPA low-dose L-DOPA
  • vehiclel that for pridopidine
  • vehicle2 that for AMT
  • AMT 5 and 10 mg/kg
  • LDh 6 mg/kg was pre defined as a dose that produces maximal levels of anti -parkinsonian benefit and rotation, but which is associated with severe / disabling levels of AIMs.
  • Vehiclel or pridopidine
  • vehicle2 or AMT
  • start of behavioural observations Rotational behaviour and AIMs, assessed for a period of 3 hours.
  • 6-OHDA 6-hydroxy dopamine
  • AIMs and rotational behavior were assessed prior to, and every twenty minutes for 3 h after treatment administration (10 assessments).
  • the 10 animals displaying the highest levels of AIMs (a minimum score of 3 for at least 3 consecutive periods of assessment) were advanced to the next study component. (Figs. 11A-D, Figs 12A-12C and Figs 13A-13C).
  • AIMs Abnormal involuntary movements
  • a score was given that denotes the maximum or highest score obtained across the observation period both for each of the subtypes individually and across all combined.
  • Figures 11A-11D present change in levels of AIMs following treatment with pridopidine at different doses, as described above.
  • Female 6-OHDA lesioned rats treated with L- DOPA once-daily for a period of 3 weeks as a model of advanced PD when motor complications have become established, followed by treatment of pridopidine at 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg doses during 3hrs.
  • the AIMs level was measured. Most robust effects were observed with 30 and 60 mg/kg.
  • Figure 11A presents change in levels of AIMs during 3 hours measured every 20 minutes at different doses of pridopidine 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg vs. vehicle.
  • Figure 11B presents a total of 20-120 min totals bars of results presented in Figure 11A.
  • the results of Figures 11A and 1 IB are also presented in Table 7.
  • Table 7 AIMs levels following treatment of pridopidine
  • Figure 11C presents net contraversive rotations of the rats during 3 hours measured every
  • Figures 12A-12C present AIMs subscores (time-courses) per 20 minutes of Limb, Axial and Orolingual following treatment with pridopidine at different doses as described above.
  • Female 6-OHDAlesioned rats treated with L-DOPA followed by treatment of pridopidine at 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg doses during 3hrs.
  • Figure 12A presents the Limb results as presented also in Table 9: Table 9: Limb results following treatment of pridopidine
  • Figure 12B presents the Axial results, as presented also in Table 10:
  • Figure 12C presents the Orolingual results, as presented also in Table 11:
  • Figures 13A-13C present AIMs subscores (20-120 min totals) bars (Limb, Axial and Orolingual) following treatment with pridopidine at different doses as presented in Figures
  • LDh 6 mg/kg were combined with vehicle 1 (that for pridopidine) and either vehicle2 (that for AMT) or AMT (5 and 10 mg/kg, SC).
  • Table 12 AIMs levels following treatment of pridopidine and AMT
  • ns no signal.
  • ns no signal.
  • Pridopidine / AMT combination produces a clear synergism such that levels of AIMs are robustly reduced to an extent that far exceeds that achievable by each agent given alone.
  • the pridopidine / AMT combination also shows a pronounced decrease in net contraversive rotations which is typical of an agent with effective anti- AIMs activity.
  • Parkinson's Disease Rating Scale Process, format, and clinimetric testing plan. Movement Disorders 22(l):41-7.
  • Parkinson's Disease Rating Scale Scale Presentation and Clinimetric Testing Results. Movement Disorders 23(15):2129-2170.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a method of treating a subject afflicted with a drug-induced movement disorder including levodopa-induced dyskinesia comprising periodically administering to the subject in need thereof an amount of pridopidine in combination with one or more additional therapeutic agent effective to treat the subject. The invention further provides a method of treating a subject at risk of developing a drug-induced movement disorder, including levodopa-induced dyskinesia. The invention also provides pharmaceutical compositions suitable for carrying out these methods and kits containing such pharmaceutical compositions.

Description

COMBINATION OF PRIDOPIDINE AND AN ADDITIONAL THERAPEUTIC AGENT FOR TREATING DRUG INDUCED DYSKINESIA
FIELD OF THE INVENTION
[001] This invention is directed to a method of treating a subject afflicted with a drug-induced movement disorder including levodopa-induced dyskinesia comprising periodically administering to the subject in need thereof an amount of pridopidine in combination with an additional therapeutic agent effective to treat the subject.
BACKGROUND OF THE INVENTION
Drug Induced Dyskinesia
[002] Dyskinesias are abnormal, involuntary movements which may appear as jerking, twisting or writhing of parts of the body. 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 (DIMDs) 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 stabilizers 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 and Levodopa-induced dyskinesia
[003] Parkinson’s disease (PD) 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.
[004] Dyskinesias are common in Parkin on’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).
[005] Levodopa (L-DOPA), the most effective agent to alleviate motor dysfunction in
Parkinson’s disease patients, is associated with the development of dyskinesias with chronic use.
As levodopa plasma half-life is very short, it is commonly administered with either benserazide or carbidopa in order to increase oral bioavailability and reduce side effects.. L-DOPA Induced
Dyskinesia (LID) is a major complication of dopamine -replacement therapy in PD (“PD-LID”; Kumar 2005, Manson 2012, Poewe 2009). Other dopamine agonist therapies may induce dyskinesia in PD patients.
[006] 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.
[007] 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‘off1 states.
[008] 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.
[009] The potential of 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. Tedroff, 2004, reported an open label, uncontrolled, self-assessed, pilot study of once a day low-dose pridopidine (20-100 mg once a day; average dose 57 mg/day) in seven advanced stage Parkinson’s disease (PD) patients. Tedroff provides no guidance for treating LID in PD patients. Since that study was disclosed with no mention of what the“regular antiparkinsonias medication” is, no controlled study has been performed to objectively assess the effect of pridopidine for treating LID in PD patients.
[0010] The value of current therapies for Parkinson’s disease (PD), particularly L-DOPA, is limited by significant complications of long-term treatment, especially L-DOPA-induced dyskinesia (LID). While amantadine (AMT) is already employed clinically for the treatment of established dyskinesia, though generally in an off-label capacity, its therapeutic utility is limited by several factors. It is poorly tolerated by many patients (40-50%) and its use is often compromised by sedation and cognitive problems.
Pridopidine
[0011] Pridopidine (formerly ACR16, Huntexil®) is a drug in development for the treatment of patients with Huntington disease. The chemical name of pridopidine base is 4-(3- (methylsulfonyl)phenyl)-l-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).
[0012] Pridopidine demonstrates a complex binding profile with high affinity binding to the sigma- 1 receptor (oiR, or SIR) (Johnston et al, 2019; 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 (Johnston et al, 2019; Ponten 2013).
[0013] 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, (Ponten 2010, Sahlholm 2015).
[0014] The SIR is an endoplasmic reticulum (ER) chaperone protein which is implicated in cellular differentiation, neuroplasticity, neuroprotection and cognitive function in the brain. Recently, transcriptomic analysis of rat striatum showed that pridopidine treatment activates expression of the brain- derived neurotrophic factor (BDNF), dopamine receptor 1 (DIR), glucocorticoid receptor (GR), and the serine-threonine kinase protein kinase B (Akt)/phosphoinositide 3 -kinase (PI3K) pathways, known to promote neuronal plasticity and survival and to be impaired in HD. Pridopidine was shown to enhance secretion of the neuroprotective BDNF in a neuroblastoma cell line, in a SIR-dependent manner (Geva 2016).
[0015] Effective treatments for LID and other drug induced movement disorders (DIMD), including drug-induced dyskinesias, remain a significant unmet need.
SUMMARY OF THE INVENTION
[0016] The present invention provides a method of treating drug-induced movement disorder (DIMD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent.
[0017] In one embodiment, 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. In one embodiment, the DIMD is selected from parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics.
[0018] The present invention provides a method of treating levodopa-induced dyskinesia (LID) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent. In one embodiment, the subject is afflicted with Parkinson’s disease. In one embodiment, the subject is afflicted with parkinsonism other than Parkinson’s disease.
[0019] The present invention further provides a method of alleviating or reducing a symptom associated with the levodopa treatment in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent. In one embodiment, the symptom is abnormal movements, myoclonic jerks, irregular movements of extremities, gait, facial grimacing, ataxia, inability to sustain motor act, hand movement or balance, choreiform peak dose dyskinesia, or dystonic peak dose dyskinesia. In one embodiment, the symptom is bad quality on-time evoked by levodopa.
[0020] In one embodiment, in the method of the invention, the one or more additional therapeutic agent is selected from the group consisting of Amantadine, Dipraglurant (ADX48621), Foliglurax, IRF790, Eltoprazine, Buspirone, Fevetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof.
BRIEF DESCRIPTION OF THE FIGURES
[0021] Figures 1-3 show the effect of pridopidine in historic studies of Huntington disease.
[0022] Figures 1A and IB: Graphs showing the effect of 45 mg bid pridopidine on Total Motor Score (TMS), full analysis set from MermaiHD (Figure 1A) and HART (Figure IB) studies, respectively. In both graphs, the upper line shows results with placebo treatment, the lower line shows results with 45 mg bid treatment.
[0023] Figure 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).
[0024] Figure 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).
[0025] Figure 4: Reproduction of a PET scan showing levels of S IR occupancy by pridopidine in the brain of healthy volunteers before (upper panel) and after (lower panel) a single dose of 45 mg pridopidine.
[0026] Figures 5-10 show the effect of pridopidine in combination with a high F-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 F-DOPA induced dyskinesia, including choreiform and dystonic dyskinesia evoked by high-dose L-DOPA without affecting the beneficial anti-parkinsonian effects of L-DOPA.
[0027] Figure 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. Figure 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.
[0028] Figure 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.
[0029] Figure 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.
[0030] Figure 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. Figure 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.
[0031] Figure 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.
[0032] Figure 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.
[0033] Figure 9A: Graph showing that pridopidine reduces L-DOPA induced dystonia (0-6 hours accumulated, study 1). Pridopidine reduces established dystonia evoked by high dose L-DOPA. Y axis is severity of dystonia, X axis shows pridopidine doses.
[0034] Figure 9B: 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.
[0035] Figure 10: Bar graph showing the effects of pridopidine on duration and quality of on-time (study 2). [0036] Figures 11A-11D present change in levels of AIMs following treatment with pridopidine at different doses, as described in Example 8. Female 6-hydroxydopamine (6-OHDA) lesioned rats treated with L-DOPA (10 mg/kg, IP) once-daily for a period of 3 weeks as a model of advanced PD when motor complications have become established, followed by treatment of pridopidine at 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg doses during 3hrs. The AIMs level was measured. Most significant results were obtained with 30 and 60 mg/kg. Figure 11A presents change in levels of AIMs over 3 hours measured every 20 minutes at different doses of pridopidine 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg vs. vehicle. Figure 11B presents a total of 20-120 min totals bars of results presented in Figure 11 A. Figure 11C presents net contraversive rotations of the rats during 3 hours measured every 20 minutes at different doses of pridopidine 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg vs. vehicle. Figure 11D presents a 20-120 min total bars of results presented in Figure 11C. P-values are presented in the corresponding tables.
[0037] Figures 12A-12C present AIMs subscores (time-courses) per 20 minutes of Fimb, Axial and Orolingual following treatment with pridopidine at different doses as described in Example 7. Female 6- hydroxydopamine (6-OHDA) lesioned rats treated with F-DOPA followed by treatment of pridopidine at 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg doses during 3hrs. Figure 12A presents the Fimb AIMs results. Figure 12B presents the Axial AIMs results. Figure 12C presents the Orolingual AIMs results.
[0038] Figures 13A-13C are bar graphs presentations of the time course shown in Figure 12, total of 20- 120 min of AIMs subscores (20-120 min totals) bars (Fimb, Axial and Orolingual) following treatment with pridopidine at different doses as presented in Figures 12A to 12C and described in Example 8. Figure 13A presents the Fimb results. Figure 13B presents the Axial results. Figure 13C presents the Orolingual results.
[0039] Figures 14A-14D present change in levels of AIMs following treatment with sub optimal dose pridopidine (15 mg/kg) with 5 mg/kg and 10 mg/kg amantadine (AMT), as described in Example 7. Female 6-hydroxydopamine (6-OHDA) lesioned rats treated with L-DOPA followed by treatment of pridopidine (15 mg/kg) and amantadine (5 mg/kg and 10 mg/kg) during 3hrs. Figure 14A presents change in levels of AIMs during 3 hours measured every 20 minutes. Figure 14B presents a total of 20-120 min total bars of results presented in Figure 14A. Figure 14C presents net contraversive rotations of the rats over 3 hours measured every 20 minutes. Figure 14D presents a 20-120 min total bars of results presented in Figure 14C.
[0040] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements. DETAILED DESCRIPTION OF THE INVENTION
[0041] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.
[0042] The present invention provides a method of treating drug-induced movement disorder (DIMD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent.
[0043] In one embodiment, the one or more additional therapeutic agent is selected from the group consisting of Amantadine, Dipraglurant (ADX48621), Foliglurax, IRL790, Eltoprazine, Buspirone, Levetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof. In another embodiment“one or more therapeutic agent” refers to one, two, three or four different therapeutic agents in addition to pridopidine.
[0044] In one embodiment, the one or more additional therapeutic agent is in its neutral form or in its salt form, such as a pharmaceutically acceptable salt.
[0045] In one embodiment, the one or more additional therapeutic agent is administered as an add on therapy. In one embodiment, the one or more additional therapeutic agent is administered in combination with pridopidine. In another embodiment, pridopidine and the additional therapeutic agent are co-formulated. In another embodiment, the pridopidine and the additional therapeutic agent are separated pharmaceutical formulations.
[0046] In one embodiment, 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. In one embodiment, the DIMD is selected from parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics. In one embodiment, the DIMD is Tardive dyskinesia or drug-induced dystonia.
[0047] In one embodiment, the DIMD comprises dyskinesia. In one embodiment, the dyskinesia is levodopa-induced dyskinesia (LID).
[0048] In one embodiment, the subject is afflicted with Parkinson’s disease. In one embodiment, the subject is afflicted with parkinsonism other than Parkinson’s disease.
[0049] In one embodiment, the subject is concurrently being treated with levodopa. In one embodiment, the pridopidine and the one or more additional therapeutic agent are administered simultaneously with the levodopa. In one embodiment, the pridopidine and the one or more additional therapeutic agent are administered after the levodopa is administered for a period of time. In one embodiment, the levodopa is administered after the pridopidine and the one or more additional therapeutic agents are administered for a period of time. In one embodiment, the period of time is from 10 min to 18 hours, for example, 10 min, 15 min, 20 min, 25 min, 30 min, 45 min, 1.0 hour, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours, 5.0 hours, 6.0 hours, 7.0 hours, 8.0 hours, 9.0 hours, 10.0 hours, 11.0 hours, 12.0 hours, 15 hours or 18 hours. In one embodiment, the period of time is 10 min, 20 min, 30 min, 45 min, 1.0 hour, 2.0 hours, 6.0 hours, or 12 hours. In another embodiment, the period of time is from 10 min to 1 hour. In another embodiment, the period of time is from 10 min to 3 hours. In another embodiment, the period of time is from 1 hour to 3 hours. In another embodiment, the period of time is from 2 hours to 5 hours. In another embodiment, the period of time is from 4 hours to 10 hours. In another embodiment, the period of time is from 6 hours to 12 hours. In another embodiment, the period of time is from 12 hours to 18 hours.
[0050] The method of the invention further alleviates or reduces a symptom associated with the levodopa treatment in a subject in need thereof. In one embodiment, the symptom is abnormal movements, myoclonic jerks, irregular movements of extremities, gait, facial grimacing, ataxia, inability to sustain motor act, hand movement or balance, choreiform peak dose dyskinesia, or dystonic peak dose dyskinesia. In one embodiment, the symptom is bad quality on-time evoked by levodopa. In one embodiment, the administration of the pridopidine and the one or more additional therapeutic agent improves the symptom of the levodopa induced dyskinesia by at least 10%, by at least 20%, by at least 30% or by at least 50% as measured by AIMS, Rush Dyskinesia Rating Scale (RDRS), MDS-UPDRS or UDysRS.
[0051] In one embodiment, the pridopidine and the one or more additional therapeutic agent are administered simultaneously or sequentially. In one embodiment, pridopidine and the one or more additional therapeutic agents are administered once daily, twice daily, three times daily, or four times daily. In one embodiment, pridopidine and the one or more additional therapeutic agents are administered less than once daily. In one embodiment, pridopidine and the one or more additional therapeutic agents are administered every other day. In one embodiment, pridopidine and the one or more additional therapeutic agents are administered once weekly or bi-weekly.
[0052] In one embodiment, the pridopidine is in the form of a pridopidine salt. In one embodiment, the pridopidine salt is pridopidine hydrochloride. In another embodiment, the pridopidine is the hydrobromide, the L-tartrate, the nitrate, the perchlorate, the phosphate, the sulphate, the formate, the acetate, the aconate, the ascorbate, the benzenesulphonate, the benzoate, the cinnamate, the citrate, the embonate, the enantate, the fumarate, the glutamate, the glycolate, the lactate, the maleate, the malonate, the mandelate, the methanesulphonate, the naphthalene-2-sulphonate, the phthalate, the salicylate, the sorbate, the stearate, the succinate, the tartrate or the toluene-p- sulphonate salt.
[0053] In one embodiment, the pridopidine which is administered with one or more additional therapeutic agent is administered at a dose of from 10 mg to 500 mg, for example, 10 mg, 15 mg, 20 mg, 22.5 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 67.5 mg, 75 mg, 100 mg, 112.5 mg, 125 mg, 135 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg. In one embodiment, the pridopidine is administered at a dose of from 10 mg to 100 mg. In one embodiment, the pridopidine is administered at a dose of from 10 mg to 20 mg. In one embodiment, the pridopidine is administered at a dose of from 10 mg to 50 mg. In one embodiment, the pridopidine is administered at a dose of from 20 mg to 80 mg. In one embodiment, the pridopidine is administered at a dose of from 10 mg to 150 mg. In one embodiment, the pridopidine is administered at a dose of from 45 mg to 150 mg. In one embodiment, the pridopidine is administered at a dose of from 10 mg to 200 mg. In one embodiment, the pridopidine is administered at a dose of from 100 mg to 300 mg. In one embodiment, the pridopidine is administered at a dose indicated above once daily, twice daily, three times daily, or four times daily.
[0054] In one embodiment, the pridopidine which is administered with one or more additional therapeutic agent is administered at a dose of 10 mg once daily, twice daily, three times daily, or four times daily. In one embodiment, the pridopidine is administered at a dose of 22.5 mg once daily, twice daily, three times daily, or four times daily. In one embodiment, the pridopidine is administered at a dose of 45 mg once daily, twice daily, three times daily, or four times daily. In one embodiment, the pridopidine is administered at a dose of 67.5 mg once daily, twice daily, three times daily, or four times daily. In one embodiment, the pridopidine is administered at a dose of 75 mg once daily, twice daily, three times daily, or four times daily. In one embodiment, the pridopidine is administered at a dose of 100 mg once daily, twice daily, or three times daily. In one embodiment, the pridopidine is administered at a dose of 112.5 mg once daily, twice daily, three times daily, or four times daily. In one embodiment, the pridopidine is administered at a dose of 120 mg once daily, twice daily, or three times daily. In one embodiment, the pridopidine is administered at a dose of 150 mg once daily, twice daily, or three times daily. In one embodiment, the pridopidine is administered at a dose of 175 mg once daily, twice daily, three times daily, or four times daily.
[0055] In one embodiment, in the method of the invention, the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Amantadine. In one embodiment, the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Amantadine. In one embodiment, the one or more additional therapeutic agent comprises Amantadine at a dose of between 10-400 mg, for example, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350, 375 mg, or 400 mg. In one embodiment, the dose of Amantadine is 10, 50, 100, 137, 150, 200, 250, 274, 300, 350, or 400 mg. In one embodiment, the one or more additional therapeutic agent comprises Amantadine at a dose of between 10-100 mg. In one embodiment, the one or more additional therapeutic agent comprises Amantadine at a dose of between 50-150 mg. In one embodiment, the one or more additional therapeutic agent comprises Amantadine at a dose of between 100-250 mg. In one embodiment, the one or more additional therapeutic agent comprises Amantadine at a dose of between 200-400 mg. In one embodiment, the Amantadine is administered once daily, twice daily, three times daily, or four times daily.
[0056] In one embodiment, in the method of the invention, the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Dipraglurant. In one embodiment, the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agents comprise Dipraglurant. In one embodiment, the one or more additional therapeutic agents comprise Dipraglurant at a dose of 10-400 mg, for example, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350, 375 mg, or 400 mg. In one embodiment, the amount of Dipraglurant is 50, 100, 200, 250, or 300 mg. In one embodiment, the one or more additional therapeutic agent comprises Dipraglurant at a dose of between 10-100 mg. In one embodiment, the one or more additional therapeutic agent comprises Dipraglurant at a dose of between 50-150 mg. In one embodiment, the one or more additional therapeutic agent comprises Dipraglurant at a dose of between 100-250 mg. In one embodiment, the one or more additional therapeutic agent comprises Dipraglurant at a dose of between 200-400 mg. In one embodiment, Dipraglurant is administered once daily, twice daily, three times daily, or four times daily.
[0057] In one embodiment, in the method of the invention, the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Foliglurax. In one embodiment, the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Foliglurax. In one embodiment, the one or more additional therapeutic agent comprises Foliglurax in a dose of between 10-50 mg, for example, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In one embodiment, the amount of Foliglurax is 10 mg, 20 mg, 30 mg, or 40 mg. In one embodiment, the Dipraglurant is administered once daily, twice daily, three times daily, or four times daily.
[0058] In one embodiment, in the method of the invention, the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises IRL790. In one embodiment, the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises IRL790. In one embodiment, the one or more additional therapeutic agent comprises IRL790 in a dose of between of 1-150 mg, for example, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, or 150 mg. In one embodiment, the amount of IRL790 is 10 mg, 18 mg, 50 mg, 100 mg, 120 mg, or 150 mg. In another embodiment, the one or more additional therapeutic agent comprises IRL790 in a dose of between of 1-50 mg. In another embodiment, the one or more additional therapeutic agent comprises IRL790 in a dose of between of 50-100 mg. In another embodiment, the one or more additional therapeutic agent comprises IRL790 in a dose of between of 75-150 mg. In one embodiment, the IRL790 is administered once daily, twice daily, three times daily, or four times daily.
[0059] In one embodiment, in the method of the invention, the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Eltoprazine. In one embodiment, the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Eltoprazine. In one embodiment, the one or more additional therapeutic agents comprises Eltoprazine at a dose of between 1-10 mg, for example, 1 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.5 mg, 8.0 mg, 9.0 mg, or 10 mg. In one embodiment, the amount of Eltoprazine is 1 mg, 2.5 mg, 5.0 mg, 7.5 mg, or 10 mg. In one embodiment, the Eltoprazine is administered once daily, twice daily, three times daily, or four times daily.
[0060] In one embodiment, in the method of the invention, the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Buspirone. In one embodiment, the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Buspirone. In one embodiment, the one or more additional therapeutic agent comprises Buspirone in an amount of 1-50 mg, for example, 1 mg, 2 mg, 2.5 mg, 3 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, or 50 mg. In one embodiment, the amount of Buspirone is 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg. In one embodiment, the Buspirone is administered once daily, twice daily, three times daily, or four times daily.
[0061] In one embodiment, in the method of the invention, the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Levetiracetam. In one embodiment, the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Levetiracetam. In one embodiment, the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 100-2000 mg. In one embodiment, the amount of Levetiracetam is 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg. In one embodiment, the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 100-300 mg. In one embodiment, the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 250-500 mg. In one embodiment, the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 350-700 mg. In one embodiment, the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 500-1000 mg. In one embodiment, the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 750-1500 mg. In one embodiment, the one or more additional therapeutic agent comprises Levetiracetam in a dose of between 750-2000 mg. In one embodiment, the Levetiracetam is administered once daily, twice daily, three times daily, or four times daily.
[0062] In one embodiment, in the method of the invention, the pridopidine is administered in combination with one or more additional therapeutic agent, wherein the one or more additional therapeutic agent comprises Nuedexta (dextromethorphan and Quinidine). In one embodiment, the one or more additional therapeutic agent is administered as an add-on therapy to pridopidine, wherein the one or more additional therapeutic agent comprises Nuedexta (dextromethorphan and Quinidine). In one embodiment, the one or more additional therapeutic agent comprises Nuedexta (dextromethorphan and Quinidine) in an amount of 1-50 mg. In one embodiment, the amount of Nuedexta (dextromethorphan and Quinidine) is 2 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In one embodiment, the Nuedexta (dextromethorphan and Quinidine) is administered once daily, twice daily, three times daily, or four times daily.
[0063] In one embodiment, in the method of the invention, the weight ratio between the pridopidine and the one or more additional therapeutic agent is from about 1:20 to about 20: 1. In one embodiment, the weight ratio between the pridopidine and the one or more additional therapeutic agent is about 1:20, about 1: 15, about 1:10, about 1:7.5, about 1:5.0, about 1:2.5, about 1:1, about 2.5:1, about 5:1, about 7.5: 1, about 10:1, about 15: 1 or about 20:1.
[0064] In some embodiments, the term“additional therapeutic agent” and the term “second compound” are used interchangeably.
[0065] Amantadine as used herein is an antiviral that is used in the prophylactic or symptomatic treatment of influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. Its chemical name is l-adamantylamine. Amantadine as used herein refers to amantadine base or any pharmaceutically acceptable salt thereof. In an embodiment, the Amantadine used herein includes the Gocovri™ formulation, the Symmetrel® formulation or the Osmolex ER™ formulation.
[0066] Dipraglurant, as used herein, has been studied in trials for the treatment of Parkinson's Disease, which has a chemical name of 6-fluoro-2-(4-pyridin-2-ylbut-3-ynyl)imidazo[l,2- a] pyridine. Dipraglurant as used herein refers to Dipraglurant base or any pharmaceutically acceptable salt thereof
[0067] Foliglurax, as used herein, has a chemical name of 4-[3-[4-nitroso-2-(5H-thieno[3,2- c]pyridin-6-ylidene)chromen-6-yl]propyl]morpholine, which is under development for the treatment of Parkinson's disease. Foliglurax as used herein refers to Foliglurax base or any pharmaceutically acceptable salt thereof.
[0068] IRF790, as used herein, is an experimental small molecule compound with psychomotor stabilizing properties and potently reduced levodopa-induced involuntary movement without impairing the antiparkinsonian effect of levodopa. IRF790 as used herein refers to IRF790 base or any pharmaceutically acceptable salt thereof
[0069] Eltoprazine, as used herein, has been used in trials studying the treatment of schizophrenia and cognitive impairment, which has a chemical name of l-(2,3-dihydro-l,4-benzodioxin-5- yl)piperazine. Eltoprazine as used herein refers to Eltoprazine base or any pharmaceutically acceptable salt thereof.
[0070] Buspirone, as used herein, is an anxiolytic agent, which has a chemical name of 8-[4-(4- pyrimidin-2-ylpiperazin-l-yl)butyl]-8-azaspiro[4.5]decane-7,9-dione. Buspirone as used herein refers to Buspirone base or any pharmaceutically acceptable salt thereof
[0071] Levetiracetam, as used herein, has antiepileptic activity. Its chemical name is (2S)-2-(2- oxopyrrolidin-l-yl)butanamide. Levetiracetam as used herein refers to Levetiracetam base or any pharmaceutically acceptable salt thereof
[0072] Nuedexta (dextromethorphan/Quinidine), as used herein, is a central nervous system agent for the treatment of PseudoBulbar Affect (PBA), a medical condition that causes involuntary, sudden, and frequent episodes of crying and/or laughing in people living with certain neurologic conditions or brain injury. Nuedexta as used herein refers to Nuedexta base or any pharmaceutically acceptable salt thereof.
[0073] 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.
[0074] This evidence is especially surprising in view of the lack of efficacy of high doses of pridopidine in improving motor function in HD patients.
[0075] The present invention further provides a method of treating LID in a subject with PD comprising administering to the subject an amount of pridopidine and one or more additional therapeutic agent 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 and one or more additional therapeutic agent 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.
[0076] 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 and one or more additional therapeutic agent effective to treat the dyskinesia in the subject.
[0077] 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 and one or more additional therapeutic agent effective to treat the DIMD. The invention also provides pridopidine and one or more additional therapeutic agent for use in treating drug-induced movement disorder (DIMD) in a subject in need thereof. In some embodiments, the DIMD comprises dyskinesia. In some embodiments the dyskinesia is levodopa- induced dyskinesia (LID). In some embodiments, 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. Certain selective serotonin reuptake inhibitors (SSRI) are known to induce DIMD (Gerber 1998, incorporated herein in its entirety by reference). In some embodiments, the DIMD is selected from parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics. [0078] 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 and one or more additional therapeutic agent effective to treat the subject. The invention provides pridopidine and one or more additional therapeutic agent for use in treating a side effect of levodopa treatment in a subject in need thereof.
[0079] 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 and one or more additional therapeutic agent, wherein the amounts when taken together are effective to treat the human subject. Further provided is pridopidine and one or more additional therapeutic agent in combination with levodopa for use in treating levodopa induced dyskinesia in a subject in need thereof. In some embodiments of the method and use, the subject is afflicted with parkinsonism. In some embodiments of the method and use, the subject is a patient afflicted with Parkinson’s disease.
[0080] 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 and one or more additional therapeutic agent effective to delay the onset of LID or reduce the risk of developing LID.
[0081] In embodiments of the method and use for treating LID in PD patients, or of the method and use of treating a subject at risk of developing LID, the amount of pridopidine (administered with one or more additional therapeutic agent) is between 10 mg/day up to 500 mg/day. In certain embodiments, the amount of pridopidine (administered with one or more additional therapeutic agent) is 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 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, 400 mg/day or 500 mg/day.
[0082] In embodiments of the method and use for treating LID, or of the method and use of treating a subject at risk of developing LID (by administering pridopidine thereof with one or more additional therapeutic agent), the AUCO-inf 24 achieved is 500 h*ng/ml to 60,000 h*ng/ml or 1,000 h*ng/ml to 5,000 h*ng/ml or 3,000 h*ng/ml to 10,000 h*ng/ml or 5,000 h*ng/ml to 12,000 h*ng/ml or 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/ml.
[0083] 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; (c) one or more additional therapeutic agent and a pharmaceutically acceptable carrier. In a further embodiment, the package also comprises (c) instructions for use of the first, second and additional therapeutic agent compositions together to treat a human subject afflicted with LID or DIMD. In some embodiments the pridopidine is provided as pridopidine base. In some embodiments the pridopidine is provided as a pridopidine salt, e.g. pridopidine HC1.
[0084] This invention additionally provides use of an amount of levodopa and an amount of pridopidine and an amount of an additional therapeutic agent 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 and the one or more therapeutic agent 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.
[0085] 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 and one or more therapeutic agent by periodically administering the pharmaceutical composition, the pridopidine and the one or more additional therapeutic agent to the subject.
[0086] This invention also provides a pharmaceutical composition comprising an amount of pridopidine and one or more additional therapeutic agent for use treating a subject afflicted with levodopa induced dyskinesia as an add-on therapy or in combination with levodopa and/or additional therapeutic agent by periodically administering the pharmaceutical composition to the subject.
[0087] In one embodiment, the methods of this invention make use of a composition comprising pridopidine or salt thereof in combination with one or more additional therapeutic agent. In another embodiment, the composition comprising pridopidine or salt thereof, further comprises at least one analog of pridopidine selected from the following structures of compounds 1-7:
Figure imgf000018_0001
Figure imgf000019_0001
[0088] In another embodiment, the composition comprising pridopidine or salt thereof, further comprises at least an analog of compound (1); or at least an analog of compound (4); or comprising analogs of compound (1) and of compound (4).
[0089] In yet another embodiment of the methods, uses and compositions, 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). In some embodiments, the dyskinesia in a subject afflicted with PD is quantified using the PD Home Diary scale. In other embodiment of the methods, uses and compositions, the dyskinesia in a subject not afflicted with PD is quantified by, for example, the Rush Dyskinesia Rating Scale (RDRS), the Unified Dyskinesia Rating Scale (UdysRS) or AIMS rating scale (Goetz 2008b, Ecdeu 1976, the entire contents of which are hereby incorporated by reference).
[0090] 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 and one or more additional therapeutic agent 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 or salt thereof and one or more additional therapeutic agent effective to treat the DIMD. In some embodiments, the DIMD comprises dyskinesia.
[0091] In an embodiment, the dyskinesia is Levodopa-Induced Dyskinesia (LID).
[0092] 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 or salt thereof and one or more additional therapeudc agent effective to treat the subject.
[0093] In another embodiment, treating comprises reducing a side effect of levodopa. In one embodiment, the side effect is dyskinesia. [0094] In some embodiments, the subject is a patient afflicted with parkinsonism. In one embodiment, the subject is a Parkinson’s disease patient. In another embodiment, the subject is an advanced stage Parkinson’ s disease patient. In a further embodiment, the subject is a patient afflicted with parkinsonism other than Parkinson’s disease.
[0095] In one embodiment, the subject is concurrently being treated with levodopa.
[0096] In an embodiment, the amount of pridopidine and one or more additional therapeutic agent 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, the one or more additional therapeutic agent and the levodopa are co-formulated. In another embodiment, the amount of pridopidine, the amount of one or more additional therapeutic agent are co-formulated. In another embodiment, the amount of pridopidine, the one or more additional therapeutic agent and the levodopa are administered sequentially and in separate pharmaceutical formulations.
[0097] In one embodiment, the amount of pridopidine is effective to alleviate or reduce a symptom associated with the levodopa treatment. In some embodiments, 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. In another embodiment, the symptom is choreiform peak dose dyskinesia, or dystonic peak dose dyskinesia. In another embodiment, the symptom is bad quality on-time evoked by levodopa.
[0098] In an embodiment, the administration of pridopidine and the one or more additional therapeutic agent 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).
[0099] In one embodiment, the anti-parkinsonian effect of levodopa is not affected by the amount of pridopidine.
[00100] In an embodiment, the dyskinesia in the subject is assessed by one or more of the following rating scales: UDysRS, Rush Dyskinesia Rating Scale (RDRS), 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). In another embodiment, the patient had a UDysRS score or UPDRS score of 10 or greater at baseline.
[00101] In some embodiments, 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. In some embodiments the DIMD is parkinsonism. In some embodiments the DIMD is tardive dyskinesia. In some embodiments the DIMD is drug-induced dystonia. In some embodiments the DIMD is tremor. In some embodiments the DIMD is akathisia. In some embodiments the DIMD is athetosis. In some embodiments the DIMD is myoclonus. In some embodiments the DIMD is tics.
[00102] In one embodiment, the pridopidine and the one or more therapeutic agent are administered via oral administration. In another embodiment, the pridopidine and the one or more therapeutic agent are administered daily. In another embodiment, pridopidine and the one or more therapeutic agent are administered twice daily. In some embodiments one-unit dose of the pridopidine is administered within 60 minutes of awakening and a second dose is administered after 6-10 hours. In another embodiment, pridopidine and the one or more therapeutic agent is administered thrice daily. In another embodiment, the pridopidine is a pridopidine salt. In another embodiment, the pridopidine salt is provided as pridopidine hydrochloride (pridopidine HC1).
[00103] In embodiments of the method or use for treating LID in PD patients, the amount of pridopidine (administered in combination with one or more additional therapeutic agent to a subject in need thereof) is between 10-500 mg/day. In another embodiment, the amount of pridopidine is 10 mg/day. 15 mg/day, 20 mg/day, 22.5 mg/day, 45 mg/day, 67.5 mg/day, 75 mg/day, 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 , 400 mg/day or 500 mg/day. In another embodiment, the amount of pridopidine administered is from above 10 mg per day to 100 mg per day. In another embodiment, the amount of pridopidine administered is from above 10 mg per day to 200 mg per day. In another embodiment, the amount of pridopidine administered is from above 100 mg per day to 300 mg per day. In another embodiment, the amount of pridopidine administered is from above 100 mg per day to 400 mg per day. In another embodiment, the amount of pridopidine administered is from above 200 mg per day to 350 mg per day. In another embodiment, the amount of pridopidine administered is from above 100 mg per day to 350 mg per day. In another embodiment, 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 tid (thrice daily), 90 mg tid, 100 mg tid, or 125 mg tid. In another embodiment, the amount of pridopidine administered is 100 mg bid (twice daily), 125 mg bid, 150 mg bid, 175 mg bid, or 200 mg bid. In preferred embodiments, the pridopidine is administered as pridopidine HC1, twice daily. [00104] In embodiments of the method or use for treating LID in PD patients, pridopidine (administered in combination with one or more additional therapeutic agent) is administered at a daily dose of between 10 mg to 500 mg given in the form of pridopidine HC1. In other embodiments, pridopidine is administered at a daily dose of 10 mg, 20 mg, 45mg, 90 mg, 135 mg, 180 mg, 225 mg, 300 mg, 350 mg, 400 mg or 500 mg given in the form of pridopidine HC1. 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.
[00105] In preferred embodiments of the method or use for treating LID in PD patients (by administering pridopidine in combination with one or more additional therapeutic agent), the AUCO-24 achieved is about 500 h*ng/ml to 60,000 h*ng/ml or 1,000 h*ng/ml to 5,000 h*ng/ml or 3,000 h*ng/ml to 10,000 h*ng/ml or 5,000 h*ng/ml to 12,000 h*ng/ml or 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/ml.
[00106] In certain embodiments of the method of treating LID in PD patients (by administering pridopidine in combination with one or more additional therapeutic agent), pridopidine is administered to a subject in need thereof in an amount to achieve an AUC0-24 plasma level of between 500 h*ng/ml to about 60,000 h*ng/ml; 1,000 h*ng/ml to 5,000 h*ng/ml, 3,000 h*ng/ml to 10,000 h*ng/ml, 5,000 h*ng/ml to 12,000 h*ng/ml, 12,000 h*ng/ml to 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 to 35,000 h*ng/ml, 20,000 h*ng/ml to 30,000 h*ng/ml, or about 13,000 h*ng/ml, 14,000 h*ng/ml, 15,000 h*ng/ml, 16,000 h*ng/ml, 17,000 h*ng/ml, 18,000 h*ng/ml, 19,000 h*ng/ml, 20,000 h*ng/ml, 21,000 h*ng/ml, 22,000 h*ng/ml, 23,000 h*ng/ml, 24,000 lrmg/ml, 25,000 h*ng/ml, 26,000 lrmg/ml, 27,000 h*ng/ml, 28,000 h*ng/ml, 29,000 h*ng/ml, 30,000 h*ng/ml, 31,000 h*ng/ml, 32,000 h*ng/ml, 33,000 h*ng/ml, 34,000 h*ng/ml, 35,000 h*ng/ml, 36,000 h*ng/ml, 37,000 h*ng/ml, 38,000 h*ng/ml, 39,000 h*ng/ml, 40,000 h*ng/ml, 41,000 h*ng/ml, 42,000 h*ng/ml, 43,000 h*ng/ml, 44,000 h*ng/ml, 45,000 h*ng/ml, 46,000 h*ng/ml, 47,000 h*ng/ml, 48,000 h*ng/ml, 49,000 h*ng/ml, 50,000 h*ng/ml, 51,000 h*ng/ml, 52,000 h*ng/ml, 53,000 h*ng/ml, 54,000 h*ng/ml, 55,000 h*ng/ml, 56,000 h*ng/ml, 57,000 h*ng/ml, 58,000 h*ng/ml, 59,000 h*ng/ml, or 60,000 h*ng/ml, In some embodiments, pridopidine is administered to a subject in need thereof in an amount to achieve an AUCo-24 plasma level of 500-60,000 h*ng/ml, 25,000 h*ng/ml to 60,000 h*ng/ml, 29,000 h*ng/ml to 59,000 h*ng/ml, or 29,000 h*ng/ml to 50,000 h*ng/ml, or about 1,000 h*ng/ml , 2,000 h*ng/ml , 3,000 h*ng/ml, 4000 h*ng/ml, 5,000 h*ng/ml to 10,000 h*ng/ml, 25,000 h*ng/ml, 26,000 h*ng/ml, 27,000 h*ng/ml, 28,000 h*ng/ml, 29,000 h*ng/ml, 44,000 h*ng/ml, 45,000 h*ng/ml, 46,000 h*ng/ml, 50,000 h*ng/ml, 51,000 h*ng/ml, or 52,000 h*ng/ml.
[00107] In some embodiments, wherein the patient is suffering from LID, the method further comprises administering to the subject a therapeutically effective amount of levodopa.
[00108] In embodiments of the method or use for treating DIMD other than LID in PD patients (by administering pridopidine in combination with one or more additional therapeutic agent), the amount of pridopidine administered to the subject is 10 mg/day, 20 mg/day, 22.5 mg/day, 45 mg/day, 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, 400 mg/day or 500 mg/day.
[00109] In embodiments of the method or use for treating DIMD other than LID in PD patients (by administering pridopidine in combination with one or more additional therapeutic agent), pridopidine is administered at a daily dose of between 10 mg-500 mg given in the form of pridopidine HC1. In another embodiment, pridopidine is administered at a daily dose of 10 mg, 15 mg, 22.5 mg, 45 mg, or 90 mg, 135 mg, 180 mg, 200 mg, 225 mg, 250 mg, 300 mg, 350 mg, 400 mg or 500 mg given in the form of pridopidine HC1. In preferred embodiments of the method or use for treating DIMD other than LID in PD patients, the daily dose of pridopidine is administered in two equal doses.
[00110] In some embodiments, for example where the subject is afflicted with LID, the method further comprises administering to the subject a therapeutically effective amount of a one or more additional therapeutic agent which is selected from the group consisting of Amantadine, Dipraglurant (ADX48621), Foliglurax, IRL790, Eltoprazine, Buspirone, Levetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof.
[00111] In some embodiments, for example where the subject is afflicted with LID, the method further comprises administering to the subject a therapeutically effective amount of a second compound which is levodopa and/or amantadine. In some embodiments, the subject is administered pridopidine and levodopa. In some embodiments, the subject is administered pridopidine and amantadine. In some embodiments, the subject is administered pridopidine, levodopa and amantadine. In an embodiment, the pridopidine and the second compound (e.g. levodopa, amantadine or levodopa and amantadine) are administered in one unit. In another embodiment, the pridopidine and the second compound are administered in more than one unit.
[00112] In one embodiment, the second compound is amantadine. In another embodiment, the amount of amantadine is 10 mg-400 mg. In another embodiment, 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. In another embodiment, the amantadine is administered orally.
[00113] In an embodiment, the second compound is levodopa. In another embodiment, 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. In another embodiment, 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.
[00114] In one embodiment, the amount of pridopidine and the amount of an additional therapeutic agent are administered simultaneously. In another embodiment, the administration of the additional therapeutic agent substantially precedes the administration of pridopidine. In another embodiment, the administration of pridopidine substantially precedes the administration of the additional therapeutic agent. In another embodiment, the subject is receiving an additional therapeutic agent therapy or levodopa therapy prior to initiating pridopidine therapy. In another embodiment, 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. In another embodiment, the subject is receiving pridopidine therapy prior to initiating receiving an additional therapeutic agent therapy or levodopa therapy. In another embodiment, 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.
[00115] In one embodiment, each of the amount of the additional therapeutic agent 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 additional therapeutic agent therapy 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 additional therapeutic agent when taken alone, the amount of pridopidine when taken alone, or each such amount when taken alone is less effective to treat the subject.
[00116] In one embodiment, the pridopidine is administered adjunctively to the additional therapeutic agent. In other embodiments, the additional therapeutic agent is administered adjunctively to the pridopidine.
[00117] In an embodiment, 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. In another embodiment, the loading dose is double the amount of the intended dose. In another embodiment, the loading dose is half the amount of the intended dose. [00118] 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 and an amount of one or more additional therapeutic agent, wherein the amounts when taken together are effective to treat the human subject.
[00119] In one embodiment, the levodopa induced dyskinesia is a peak dose dyskinesia. In another embodiment, the levodopa induced dyskinesia is diphasic dyskinesia.
[00120] In one embodiment, the amount of levodopa and the amount of pridopidine and the amount of the one or more additional therapeutic agent, when taken together are effective to reduce a symptom of the levodopa induced dyskinesia in the human subject. In another embodiment, the symptom is abnormal movements, myoclonic jerks, irregular movements of extremities, gait, facial grimacing, ataxia, inability to sustain motor act, hand movement or balance. In another embodiment, 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). In yet another embodiment, the patient had an mMS score of 10 or greater at baseline. In another embodiment, the subject is afflicted with parkinsonism other than PD parkinsonism and the subject’s motor function is assessed by the UDysRS.
[00121] In an embodiment of the present invention, the administration of levodopa and pridopidine and one or more additional therapeutic agent, improves a symptom of the levodopa induced dyskinesia by at least 4%. In an embodiment of the present invention, the administration of levodopa and pridopidine and one or more additional therapeutic agent, improves a symptom of the levodopa induced dyskinesia by at least 5% In an embodiment of the present invention, the administration of levodopa and pridopidine and one or more additional therapeutic agent, 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 and one or more additional therapeutic agent, improves a symptom of the levodopa induced dyskinesia by at least 20%. In another embodiment, the administration of levodopa and pridopidine and one or more additional therapeutic agent, improves a symptom of the levodopa induced dyskinesia by at least 30%. In another embodiment, the administration of levodopa and pridopidine and one or more additional therapeutic agent, improves a symptom of the levodopa induced dyskinesia by at least 50%. In another embodiment, the administration of levodopa and pridopidine and one or more additional therapeutic agent, improves a symptom of the levodopa induced dyskinesia by more than 100%. In another embodiment, the administration of levodopa and pridopidine and one or more additional therapeutic agent, improves a symptom of the levodopa induced dyskinesia by more than 300%. [00122] In one embodiment, the human subject is receiving levodopa therapy prior to initiating pridopidine therapy. In another embodiment, the administration of levodopa and/or one or more additional therapeutic agent, 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.
[00123] In one embodiment, 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.
[00124] In one embodiment, the amount of levodopa administered is about 50 mg to 8,000 mg/day. In one embodiment, pridopidine is administered orally. In another embodiment, pridopidine is administered through a nasal, inhalation, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route. In another embodiment, the pridopidine is administered daily. In another embodiment, the pridopidine is administered more often than once daily. In another embodiment, the administration of pridopidine is effected twice a day. In another embodiment, the pridopidine is administered less often than once daily.
[00125] In one embodiment, the one or more therapeutic agent is administered orally. In another embodiment, the one or more therapeutic agent is administered through a nasal, inhalation, subcutaneous, intravenous, intraperitoneal, intramuscular, intranasal, buccal, vaginal, rectal, intraocular, intrathecal, topical or intradermal route. In another embodiment, the one or more therapeutic agent is administered daily. In another embodiment, the one or more therapeutic agent is administered more often than once daily. In another embodiment, the administration of the one or more therapeutic agent is effected twice a day. In another embodiment, the one or more therapeutic agent is administered less often than once daily.
[00126] In some embodiment, the pridopidine and the one or more therapeutic agent are in tablet form. In one embodiment, the pridopidine and the one or more therapeutic agent are in the form of an aerosol or inhalable powder. In one embodiment, the pridopidine and the one or more therapeutic agent are in liquid form. In one embodiment, the pridopidine and the one or more therapeutic agent are in solid form. In one embodiment, the pridopidine and the one or more therapeutic agent are in capsule form.
[00127] In embodiments for the treatment of LID or for the use in the treatment of LID, the amount of pridopidine (in combination with one or more therapeutic agent) administered is between 10-500 mg/day. In another embodiment, the amount of pridopidine administered is between 10-20 mg/day. In another embodiment, the amount of pridopidine administered is between 10-100 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 150-500 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. In another embodiment, the amount of pridopidine administered is 200-500 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. In another embodiment, the amount of pridopidine administered is 500 mg/day.
[00128] In embodiments for the treatment of DIMD other than LID or for the use in the treatment of DIMD other than LID, the amount of pridopidine (in combination with one or more therapeutic agent) administered is betweenl0-500 mg/day. In another embodiment, the amount of pridopidine administered is between 10-20 mg/day. In another embodiment, the amount of pridopidine administered is between 10-100 mg/day. In another embodiment, the amount of pridopidine administered is between 30-200 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. 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 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 10 mg/day. In another embodiment, the amount of pridopidine administered is about 20 mg/day. In another embodiment, the amount of pridopidine administered is about 90 mg/day.
[00129] In one embodiment, the method further comprises administration of a one or more therapeutic agent which is an antidepressant, a psychotropic drug, an antipsychotic, amisulpride, haloperidol, olanzapine, risperidone, sulpiride, or tiapride. In an embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for at least 3 days. In another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for more than 30 days. In another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for more than 42 days. In another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for 8 weeks or more. In another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for at least 12 weeks. In another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for at least 24 weeks. In another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for more than 24 weeks. In yet another embodiment, the periodic administration of the one or more additional therapeutic agent and pridopidine continues for 6 months, or 12 months or more.
[00130] 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.
[00131] This invention also provides a pharmaceutical composition comprising an amount of levodopa and/or amantadine and an amount of pridopidine. In one embodiment, the pharmaceutical composition is in the form of an aerosol or inhalable powder. In an embodiment, the pharmaceutical composition is in liquid form. In an embodiment, the pharmaceutical composition is in solid form. In an embodiment, the pharmaceutical composition is in capsule form. In an embodiment, the pharmaceutical composition is in tablet form.
[00132] 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.
[00133] 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.
[00134] For the foregoing embodiments, each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. For instance, the elements recited in the method embodiments can be used in the pharmaceutical composition, package, and use embodiments described herein and vice versa.
[00135] All combinations, sub-combinations, and permutations of the various elements of the methods and uses described herein are envisaged and are within the scope of the invention. Terms
[00136] As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below.
[00137] The articles“a”,“an” and“the” are non-limiting. For example,“the method” includes the broadest definition of the meaning of the phrase, which can be more than one method.
[00138] As used herein,“effective” as in an amount effective to achieve an end means the quantity of a component that is sufficient to yield an indicated therapeutic response. For example, an amount effective to reduce a symptom of LID in a Parkinson’ s disease (PD) patient. The specific effective amount varies with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives. In a preferred embodiment, administration of an effective amount of a therapeutic compound is 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.
[00139] In some embodiments, 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.
[00140] 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).
[00141] As used herein, to“treat” or“treating” encompasses reducing a symptom, inducing inhibition, regression, or stasis of the disorder and/or disease. As used herein,“inhibition” of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject. In one embodiment“treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment,“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. In yet another embodiment, “treating” or“treatment” refers to delaying the onset of the disease or disorder.
[00142] “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). In an embodiment, the subject is a human adult. In an embodiment, the subject is a human adult having a mass of 70 kg.
[00143] “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.
[00144] As used herein,“periodic administration” means repeated/recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times a week and so on, etc.
[00145] As used herein, “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.
[00146] As used herein, “pridopidine” means pridopidine base or a pharmaceutically acceptable salt thereof, as well as derivatives or analogs thereof, 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. In certain embodiments, pridopidine is provided as a pharmaceutically acceptable salt, such as the HC1 salt or tartrate salt. Preferably, in any embodiments of the invention as described herein, 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.
[00147] As used herein, 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. Thus, when in the form of a salt, e.g. a pridopidine hydrochloride, 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. Similarly, when in the form of a deuterium-enriched derivative, 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. To exemplify, the factor for converting mass of pridopidine HC1 to mass of pridopidine base is 0.885 (e.g. 1 mg pridopidine HC1 x 0.885 mg pridopidine base). Accordingly, 112.99 mg/day dose of pridopidine HC1 is equivalent to a 100 mg dose of pridopidine base.
[00148] By any range disclosed herein, it is meant that all hundredth, tenth and integer unit amounts within the range are specifically disclosed as part of the invention. Thus, for example, 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. By 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. Thus, for example, 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.
[00149] It is to be appreciated that certain features of the disclosure which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any combination. Further, reference to values stated in ranges includes each and every value within that range.
[00150] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list and every combination of that list is to be interpreted as a separate embodiment. For example, a list of embodiments presented as "A, B, or C" is to be interpreted as including the embodiments, "A," "B," "C," "A or B," "A or C," "B or C," or "A, B, or C."
[00151] As used herein,“levodopa” means L-3,4-dihydroxyphenylalanine (levodopa or L- DOPA) levodopa or a pharmaceutically acceptable salt thereof, as well as derivatives. [00152] As used herein, the term "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.
[00153] As used herein, the term "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.
[00154] As used herein, the term "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.
[00155] As used herein, the term "AUC" refers to the area under the plasma, serum or blood concentration versus time curve. “AUCo-t” refers to the area under the plasma, serum or blood concentration versus time curve wherein t (hours) is the last measured time point.“AUCinfmity” refers to the area under the plasma, serum or blood concentration versus time curve extrapolated to infinity. AUC24,ss refers to area under the concentration-time curve from 0 to 24 hours at steady state. Units are presented as h*ng/ml.
Pharmaceutically Acceptable Salts
[00156] 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.
[00157] A“salt thereof’ is a salt of the instant compound which has been modified by making acid or base salts of the compound. The term“pharmaceutically acceptable salt” in this respect, 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.
[00158] 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 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. Such salts may be formed by procedures well known and described in the art. In certain embodiments, pridopidine is provided as a pharmaceutically acceptable salt, such as the HC1 salt or tartrate salt. Preferably, in any embodiments of the invention as described herein, the pridopidine is in the form of its hydrochloride salt.“Deuterium-enriched” means that the abundance of deuterium at any relevant site of the compound is more than the abundance of deuterium naturally occurring at that site in an amount of the compound. The naturally occurring distribution of deuterium is about 0.0156%. Thus, in a“deuterium-enriched” compound, 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. In some embodiments, the methods, uses, packages and kits include deuterated pridopidine.
Pharmaceutical Compositions
[00159] While 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.
[00160] In an embodiment, 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.
[00161] 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 drage, 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. Add-On/Combination Therapy
[00162] When the invention comprises a combination of the active compound and an additional one, or more, therapeutic and/or prophylactic ingredients, 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:
- as a combination that is part of the same medicament formulation, the two or more active compounds being then administered simultaneously, or
- as a combination of two or more units, each with one of the active substances giving rise to the possibility of simultaneous, or contemporaneous administration.
[00163] As used herein,“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 an additional therapeutic agent (for example, levodopa, amantadine or combination of levodopa and amantadine). In this case, 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 one or more additional therapeutic agent at the same time, or at times sufficiently close together that a synergistic activity relative to the activity of either pridopidine alone the additional therapeutic agent alone is observed or in close enough temporal proximately to allow the individual therapeutic effects of each agent to overlap.
[00164] As used herein,“add-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. For example, adding pridopidine or pridopidine and an additional therapeutic agent therapy to a Parkinson’s disease patient already receiving levodopa therapy. The FDA has recently approved extended release amantadine (Gocovri™; previously ADS-5102) for treating LID in patients with Parkinson’s disease.
[00165] As used herein,“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 Prescribes’ 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. [00166] In one example, 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. In one example, immediate release formulations of amantadine are administered in the morning and afternoon and pridopidine is administered in the morning, afternoon and early evening. In another embodiment, the extended release formulation of amantadine is OSMOLEX® ER or GOCOVRI® Optionally, levodopa is administered to the subject.
[00167] Parkinson's disease (PD) 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. 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: a-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.
[00168] Along with rigidity and bradykinesia, certain types of dyskinesia, e.g. tremor, 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) In another embodiment, by the Rush Dyskinesia Rating Scale (RDRS).
[00169] 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.
[00170] The symptoms of PD are most commonly treated with levodopa. However, use of levodopa is often complicated with dyskinesia that is caused by levodopa, mitigating its beneficial effects. 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, on the other hand, is related to administration of L-DOPA and incorporates chorea, dystonia, akathisia, athetosis, tics, myoclonus. Akathisia and dystonia are not seen in PD patients not treated with L- DOPA. These specific dyskinetic features of LID are measured by the Unified Dyskinesia Rating Scale (UDysRS), or Rush Dyskinesia Rating Scale (RDRS). The UDysRS, having both subjective and objective dyskinesia ratings, rate all aspects of LID including features such as chorea and dystonic movements (Goetz 2013, the entire contents of which are hereby incorporated by reference).
[00171] 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. 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).
[00172] LID is the most common cause of medication-induced movement disorder. However, drug-induced movement disorders (DIMDs) can be elicited by several kinds of pharmaceutical agents which modulate dopamine neurotransmission as well as other neurotransmission in the central nervous system such as serotonin, adrenaline and acetylcholine. The major groups of drugs responsible for DIMDs include antidepressants, antipsycho tics (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. The term “Parkinson’s disease levodopa-induced dyskinesia;”“levodopa-induced dyskinesia,” or“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. The most common types of 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).
Other Drug-Induced Movement Disorders (DIMD)
[00173] 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.
[00174] 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. Although the pathophysiologic mechanism of TD is unknown, it is believed that prolonged administration of 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). Drugs that increase or enhance the dopamine response, especially indirect dopamine agonists, can aggravate the disorder and the use of such drugs in neuroleptic therapy is typically avoided. (Bezchibnyk-Butler & Remington, Can J. Psych. 39:74, 1994).
[00175] 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.
[00176] Drug-induced Tourette syndrome (TS) 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
[00177] Non-limiting examples of drugs that can induce movement disorders (DIMD) 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 (Vesprin), and trimeprazine (Temaril).
[00178] As used herein, “effective” when referring to an amount of pridopidine (or pridopidine and an additional therapeutic agent) refers to the quantity of pridopidine (or the quantities of pridopidine and an additional therapeutic agent) that is sufficient to yield a desired therapeutic response.
[00179] In some embodiments, pridopidine and an additional therapeutic agent are administered with acetophenazine (Tindal). In some embodiments, pridopidine and an additional therapeutic agent are administered with amoxapine (Asendin). In some embodiments, pridopidine and an additional therapeutic agent are administered with chlorpromazine (Thorazine). In some embodiments, pridopidine and an additional therapeutic agent are administered with fluphenazine (Permitil, Prolixin). In some embodiments, pridopidine and an additional therapeutic agent are administered with haloperidol (Haldol). In some embodiments, pridopidine and an additional therapeutic agent are administered with loxapine (Loxitane, Daxolin). In some embodiments, pridopidine and an additional therapeutic agent are administered with mesoridazine (Serentil). In some embodiments, pridopidine and an additional therapeutic agent are administered with metaclopramide (Reglan). In some embodiments, pridopidine and an additional therapeutic agent are administered with molinndone (Lindone, Moban). In some embodiments, pridopidine and an additional therapeutic agent are administered with perphanzine (Trilafrom, Triavil). In some embodiments, pridopidine and an additional therapeutic agent are administered with piperacetazine (Quide). In some embodiments, pridopidine and an additional therapeutic agent are administered with prochlorperzine (Compazine, Combid). In some embodiments, pridopidine and an additional therapeutic agent are administered with promazine (Sparine). In some embodiments, pridopidine and an additional therapeutic agent are administered with promethazine (Phenergan). In some embodiments, pridopidine and an additional therapeutic agent are administered with thiethylperazine (Torecan). In some embodiments, pridopidine and an additional therapeutic agent are administered with thioridazine (Mellaril). In some embodiments, pridopidine and an additional therapeutic agent are administered with thiothixene (Navane). In some embodiments, pridopidine and an additional therapeutic agent are administered with trifluoperazine (Stelazine). In some embodiments, pridopidine and an additional therapeutic agent are administered with triflupromazine (Vesprin). In some embodiments, pridopidine and an additional therapeutic agent are administered with trimeprazine (Temaril).
Parkinson’s Disease Rating Scales
[00180] Several rating scales have been developed to measure involuntary movements in subjects afflicted with movement disorders, including parkinsonism, and PD patients. For example, the Unified Dyskinesia Rating Scale (UDysRS) was developed to evaluate involuntary movements often associated with treated Parkinson’s disease. (Unified Dyskinesia Rating Scale (UDysRS), 2008, the entire content of which is hereby incorporated by reference). 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. There are two primary sections:
a) Historical [Part 1 (On-Dyskinesia) and Part 2 (Off-Dystonia)]
b) Objective [Part 3 (Impairment) and Part 4 (Disability)]
[00181] 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.” [00182] 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”
[00183] 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).
[00184] Rush Dyskinesia Rating Scale (RDRS), developed by the Movement Disorder Society (MDS), was created to objectively assess severity of overall dyskinesia based on interference in activities of daily living, to distinguish between chorea, dystonia, and other types of dyskinesia observed and to identify the most disabling form of dyskinesia.
[00185] 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-III 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 III (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.
[00186] The following measures may be used to assess efficacy of pridopidine in treating
DIMD: change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 through 7) from baseline to end of long-term therapy (Week 54) as assessed by blinded central video rating; proportion of subjects who are a treatment success at the end of long-term therapy (Week 54), based on the Clinical Global Impression of Change (CGIC) (in which a treatment success is defined as Much or Very Much Improved); change in the modified Craniocervical Dystonia (CDQ-24) score from baseline of this study to the end of long-term therapy (Week 54); proportion of subjects who have a 50% or greater reduction in AIMS score from baseline of this study to the end of long term therapy (Week 54); proportion of subjects who are a treatment success at the end of long-term therapy (Week 54), based on the Patient Global Impression of Change (PGIC) (in which a treatment success is defined as Much or Very Much Improved); percent change in AIMS score from Baseline of this study to the end of long term therapy (Week 54); and based on the change in AIMS score from baseline of this study to the end of long-term therapy (Week 54), as assessed by blinded central video rating, the cumulative proportion of responders ranging from a 10% improvement from baseline to a 90% improvement from baseline in steps of 10 percentage points. The Hauser PD diary is a valuable tool to assess on/off time in PD patients. (Hauser 2004).
[00187] Rating scales including UPDRS, RDRS, 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.
[00188] For all studies, the patient and independent rater may be independently blinded or not blinded. In some embodiment, patient and rater are blinded.
[00189] 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. For example, 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.
[00190] “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. As used herein,“substantially precedes administration” means that the administration of one agent precedes another agent; and the two agents are not administered simultaneously or contemporaneously.
[00191] 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.
[00192] It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention. For example,“0.1-2.5mg/day” includes 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, etc. up to 2.5 mg/day.
[00193] Throughout this application, various publications are referred to by first author and year of publication. Full citations for these publications are presented in a References section immediately before the claims. Disclosures of the documents and publications cited and those in the References section are hereby incorporated by reference in their entireties into this application in order to more fully describe the state of the art as of the date of the invention described herein. [00194] This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.
EXAMPLES EXAMPLE 1
Historic results from MermaiHD, HART and PRIDE-HD clinical trials
[00195] Pridopidine has been evaluated for the treatment of motor symptoms in patients with Huntington’s Disease (HD), in three large scale clinical trials. The first two trials, MermaiHD and HART demonstrated that pridopidine, at a dose of 45 mg twice daily (bid) (90 mg/day) significantly improved motor function in HD patients, as measured by the Unified Huntington Disease Rating Scale (UHDRS) Total Motor Score (TMS) (Figs. 1A and IB, MermaiHD and HART, respectively. Upper grey line placebo, lower black line 45mg bid pridopidine) (de Yebenes 2011; Huntington Study Group HART investigators 2013; the entire contents of which are hereby incorporated by reference).
[00196] Based on these results, it was hypothesized that high doses of pridopidine would be more efficacious than low doses in alleviating HD motor symptoms. 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. The primary outcome was pridopidine effect on motor function as assessed by the UHDRS-TMS, and exploratory endpoints including Total Functional Capacity (TFC), the most widely accepted tool for assessing disease stage were measured (Shoulson and Fahn 1979; Marder 2000). In the PRIDE-HD study, patients treated with 45mg bid pridopidine showed a similar improvement in TMS as in HART and MermaiHD. However, none of the high doses of pridopidine (>67.5 bid) showed improved efficacy compared to placebo or the 45 mg bid dose.
[00197] Post hoc analysis, at week 52, in very early stage HD patients (HD stage 1, baseline TFC >11) revealed there was a trend towards improvement in TMS change from baseline in the 45 mg bid dose treatment compared with placebo at weeks 26 or 52. However, no improvement with the high dose (112.5 mg bid) vs placebo was observed (Fig. 2, 52 weeks). A decrease in TMS (i.e. greater negative value) indicates improvement. [00198] In the TFC pre-specified exploratory endpoint, patients receiving 45 mg bid pridopidine had significantly less decline in the TFC score compared with those receiving placebo at 52 weeks [difference: 0.87 (95% confidence interval: 0.29-1.45), nominal p=0.003] (Fig. 3). Again, the high dose (>90 mg bid) failed to show improvement in TFC decline. An increase in TFC (i.e. higher value) indicates improvement.
[00199] It was concluded from the PRIDE-HD study, that the therapeutic effects in HD patients were lost at the high dose, which was similar to placebo.
EXAMPLE 2
Human Positron Emission Tomography (PET) Study
[00200] A phase 1, open label study aimed to evaluate sigma- 1 and dopamine-2 receptor (S IR and D2R, respectively) occupancy in the human brain of healthy volunteers (HV) and Huntington’s disease (HD) patients two hours after oral administration of immediate release (IR) pridopidine.
[00201] The tracer (S)-(-)-[18F]fluspidine (Brust 2014) was used to evaluate S IR 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 S IR, and 90 mg was used for D2R occupancy.
[00202] To minimize variability associated with the potential impact of circadian corticoid plasma level changes, individual scan and re-scan sessions were performed at comparable times of the day for all subjects.
[00203] The study consisted of a screening period of up to 8 weeks prior to first dosing of tracer, including a T1 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). During the study period, 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.
[00204] 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. Results:
[00205] The results of the imaging analysis show a SIR 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.
[00206] Furthermore, at a dose level of 90 mg pridopidine, no differences were observed in drug-induced S IR occupancy between HV and HD patients. Fig. 4 is a PET scan showing levels of S IR 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.
[00207] There was only minimal D2R blockage (3%) at the 90 mg pridopidine dose, which was only borderline significant, and quantitatively negligible.
[00208] The beneficial effects of pridopidine in complex pathologies such as DIMD may be mediated by its interaction with both the S IRs and the low affinity dopamine receptors (i.e. D2R).
[00209] According to the human PET data, pridopidine at 45 mg bid selectively occupies the S IR and not the low affinity targets. In order to modulate the low-affinity CNS receptors implicated in LID, pridopidine doses equivalent to about 100 mg - 175 mg bid (200-350 mg/day) were tested in non-human primates (NHP). These doses reached AUCo-24 levels above 29,000 h*ng/ml, thereby targeting the low affinity receptors.
EXAMPLE 3
Non-Human primate (NHP) model of Parkinson’s disease
[00210] The potential of 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 pmole/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 AUCo-24 levels of -12000 h*ng/ml which corresponds closely to the AUCo-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 S IRs with minimal occupancy of the dopamine receptors (DARs).
[00211] The pharmacokinetic (PK) profile and effects of pridopidine (7, 15, 20 and 30 mg/kg, PO) on parkinsonism, dyskinesia (chorea and dystonia) and quality of on-time, in combination with L-DOPA, were assessed in eight female MPTP-lesioned macaques with stable and reproducible LID. The correlation between plasma levels of pridopidine and S 1R/D2R receptor occupancies was assessed using both PK data and in-vitro/in-vivo binding data.
[00212] The study was conducted in two separate experiments. Study 1 evaluated the effects of pridopidine at 7 and 20 mg/kg in combination with L-DOPA on MPTP-lesioned macaques. In the second study, pridopidine at 15, 20 and 30 mg/kg in combination with L-DOPA was tested. In the first study (study 1) pridopidine was administered 1 hour before L-DOPA. In the second study (study 2) pridopidine was administered 2 hours before L-DOPA.
Material and Methods
[00213] Pridopidine hydrochloride (HC1) (4-[3-(Methylsulfonyl)phenyl]-l- propylpiperidine hydrochloride ), MW 317.87 g/mol, highly soluble in water was obtained. For in-vivo PK and behavioral studies, 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.
[00214] In vitro binding: In vitro binding studies were performed at Eurofins Panlabs Taiwan, Ltd to evaluate IC50/Ki values for affinity of pridopidine to sites including sΐ, s2, adrenergic a2C, a2A, 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).
[00215] 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 MathlQTM (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 MathlQTM. 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.
Pharmacokinetic profiling of pridopidine in the macaque
[00216] Blood sampling: On days of treatment, administration and plasma sampling, macaques were transferred from their home cages and seated in individual primate chairs. Four doses of pridopidine (7, 15, 20 and 30 mg/kg, N=8 per dose), were administered via oral gavage and nine blood samples for drug level analysis collected at 10 minutes prior to drug administration (t=- 10 min) and then 10 and 30 min, 1, 2, 4, 6, 8 and 24 h post drug administration. All eight animals received each of the four treatments according to a non-randomized ascending dose design, each separated by a period of one-week. Blood samples (0.5 ml) were placed into K2- EDTA tubes (Becton Dickinson, Mississauga, ON, Canada) and centrifuged at 4°C for 5 min at 1500 gave and plasma analyzed for pridopidine via LC/MS/MS.
[00217] Bioanalysis of pridopidine in macaque plasma: Pridopidine and its internal standard, 4-(3-methylsulfonyl)phenyl)-l-(propyli 7)-piperidin-l-ium chloride, were extracted from EDTA plasma by liquid-liquid extraction into acetonitrile as follows: An aliquot of 20 pi of plasma was added to 80 mΐ of acetonitrile containing 1-10 ng/ml of the internal standard (IS). After centrifuging at 13000 rpm for 8 min, 70 mΐ of supernatant was isolated and added to 70 mΐ of sterile water. Finally, an aliquot of 1-10 mΐ of the mixture was injected into the LC-MS/MS system. For all bioanalytical work 4-(3-methylsulfonyl)phenyl)-l-(propyl<i7)-piperidin-l-ium chloride was used as the internal standard. In brief, LC-MS/MS analyses were performed on a Shimadzu LC-10AD pump equipped with a CTC-HTS auto-sampler (Zwingen, Switzerland) and a column oven.
[00218] The MS/MS system was an MDS Sciex API-4000 mass spectrometer with an electrospray ionization probe (Toronto, Canada). Chromatographic separation of the analytes was achieved on an Agilent Zorbax SB-C18 column. 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 ) was calculated as 1h(2)/lz. The maximum observed plasma concentration (Cmax) and time to reach Cmax (tmax) were obtained directly from the concentration-time data. Area under the plasma concentration -versus -time curve from time 0 to 24h post dose (AUCo-24) was calculated by means of linear trapezoidal linear log interpolation regression analysis.
[00219] The pharmacokinetic profile of pridopidine was also characterized in plasma samples collected at multiple time -points up to 24h 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 S IR / D2/3R receptor occupancy.
Behavioral assessment in the MPTP -lesioned macaques
[00220] Animals: Eight cynomolgus monkeys (Macaca fascicularis, 8-14 years of age, 3.0- 4.8 kg, Suzhou Xishan-Zhongke Laboratory Animal Company, PRC) were used in this study.
[00221] Fresh fruit, primate pellets and water were available ad libitum other than at times of overnight fasting (from 5 pm) prior to days of behavioral assessment. The housing rooms were subject to a 12-hour light-dark cycle (lights on 7 a.m.), 20-25 °C in a room containing only animals of the same sex.
[00222] 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, were evoked by chronic L-DOPA treatment (25 mg/kg, Madopar™, Roche, L-DOPA: benserazide, ratio 4: 1) for at least 4-months. During this same period 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.
[00223] 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.
[00224] Treatments: The assessment of the anti-dyskinetic potential of pridopidine was undertaken in two independent experiments, both of which utilized acute challenge randomized designs. In the first study (study 1), L-DOPA (LDh, PO) was assessed alone or in combination with two doses of pridopidine (7 and 20 mg/kg, PO). In the second study (study 2), L-DOPA (LDh, PO) was assessed alone or in combination with three doses of pridopidine (15, 20 and 30 mg/kg, PO). For both studies, on the day before behavioral observations, food was removed overnight, from 5 p.m. On days of behavioral assessment, treatments were administered to the animals in their home cages. Animals were then transferred to an observation cage for behavioral assessment. Based on the outcome of the PK arms it was decided that 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).
[00225] Assessment of parkinsonian disability, dyskinesia (chorea and dystonia) and activity: Animals were transferred to individual observation cages (1.5 x 1.0 x 1.1 m) and their behavior recorded on HD-video. Rating scales for parkinsonism and dyskinesia adapted from their clinical counterparts (UPDRS pt. Ill and UDysRS respectively) were used to assess recordings via post-hoc analysis by a movement disorders neurologist blinded to treatment. A measure of total parkinsonian disability as described previously (Johnston 2013) was derived by adding scores for range of movement (score 0-4), bradykinesia (0-3), posture (0-2) and alertness (0-1). 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.
[00226] The duration of anti-parkinsonian action, on-time, was defined as the number of minutes for which the bradykinesia score was zero. In addition, 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.
[00227] Statistical analyses: Data derived from assessment of duration and quality of on- time were plotted as mean ± s.e.m. Statistical analyses for these data were performed using parametric repeated measures one- or two-way ANOVA as appropriate, followed by Holm-Sidak multiple comparison’s tests. Data for measures of parkinsonian disability and dyskinesia were graphed, where appropriate, as median scores alone (time course) or box and whisker plots (cumulated totals). Time course data for parkinsonian disability and dyskinesia were first ranked within each animal across all treatments using Excel’s RANKAVG function. These transformed data were then analyzed in GraphPad Prism (v 7.02) and subjected to non-repeated measures 2- way ANOVA followed by Holm-Sidak multiple comparison tests. Cumulated disability and dyskinesia data were analyzed using a Friedman test followed by a Dunn’s Multiple Comparisons test.
Results:
In vitro pridopidine receptor binding profile.
[00228] 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 S IR with an IC50 of 0.14 mM (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.
Table 1
Figure imgf000049_0001
IC5o= half maximum inhibitory concentration Ki = inhibition constant calculated using the equation of Cheng and Prusoff. nH = Hill coefficient, defining the slope of the competitive binding curve, was calculated using MathlQTM.
Pharmacokinetic profile of pridopidine in the MPTP-lesioned macaque
[00229] 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 mM, respectively) and AUCO-24 values of 1214, 4905, 8207 and 22987 ng*h/ml (corresponding to 4.3, 17.5, 29.2 and 81.8 h*pM)
[00230] S 1R 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.
Table 2: Expected Occupancy of Rodent and NHP SIR and D2R at Pridopidine Doses
Figure imgf000050_0001
[00231] The non-human primate (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 s 1 R 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 s 1 R occupancy data are extrapolated from in vitro binding investigations with 3H-fluspidine, known and specific s 1 R tracer, against human s 1 R. [00232] It is speculated that at the low doses (7, 15 mg/kg), pridopidine's effect is mainly mediated by the SIR, while at the higher dose (30 mg/kg and 20 mg/kg (study 1), pridopidine binds the SIR as well as a more complex activity of pridopidine is initiated by binding to the additional low affinity receptors.
[00233] 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 Figures 5-10.
In-Vivo Receptor Occupancy Profile of Pridopidine in the MPTP -Lesioned Macaque
[00234] The GI R and D2R occupancies was estimated using (i) known binding-affinities of pridopidine to human and rodent receptors in-vitro; (ii) published in-vivo PET imaging in rats and PET imaging in monkeys, and; (iii) the extensive PK profiling of pridopidine in the different species. A summary of these data is shown in Table 2A:
[00235]
Table 2A. Expected occupancy of the human and NHP receptors at various pridopidine doses.
Figure imgf000052_0001
Cmax values for NHP as a function of oral pridopidine dose are based on internally accumulated PK data (supplementary) in addition to data presented here. NHP D2R occupancy data is based on in vivo PET imaging with pridopidine (SC) the specific D2R ligand uC-raclopride. Human D2R data is estimated based on NHP data. NHP and human oiR occupancy data are extrapolated from in vitro binding investigations with 3H-fluspidine, known and specific GI R tracer, against human GIR. [00236] Table 3 shows the 6 hours data presented in Fig. 5A for Dyskinesia (time course) in study 2. Pridopidine reduces established dyskinesia evoked by high L-DOPA.
Table 3
Figure imgf000053_0001
ns: not significant. */**/*** represents P<0.05, P<0.01 or P<0.001 cf. vehicle-treatment. 2-way RM ANOVA with Holm-Sidak's test or Friedman test with DUNN'S test.
Pridopidine reduced established L-DOPA-induced dyskinesia in the MPTP-lesioned macaque [00237] Pridopidine produced a significant and dose-dependent reduction in dyskinesia evoked by LDh. Examining the whole 6hr time-course revealed a significant effect of combination treatment (F (3, 28) = 4.981, P=0.0068) but not time (F (5, 140) = 0, P>0.9999) or the interaction of treatment and time (F (15, 140) = 0.9595, P=0.5011) on levels of dyskinesia (2- way, RM-ANOVA). Compared to LDh-vehicle treatment, there was a significant decrease in dyskinesia during the first hour (20 mg/kg) and first and second hours (30 mg/kg) after start of observation in response to LDh when combined with pridopidine, with median levels remaining between moderate and marked (20 mg/kg) or mild to moderate (30 mg/kg) (all P<0.05) (Table 3). Assessing levels of dyskinesia cumulated over the two-hour period after start of observations (0-2 h period) revealed a significant effect of pridopidine combination treatment (0-2 h; Friedman Statistic (FS) = 11.66, P=0.0087, Fig. 5B) on levels of dyskinesia evoked by LDh. Median levels of dyskinesia in LDh-treated animals combined with high-dose pridopidine (30 mg/kg) were reduced by 71% compared to those seen following LDh-vehicle such that median levels were below mild (non-disabling) (P<0.01).
[00238] 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).
[00239] 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). Table 4: Pridopidine had no adverse effect on the anti-parkinsonian benefit of L-DOPA
Figure imgf000054_0001
ns: not significant
[00240] Levels of dyskinesia (Fig. 5) and parkinsonism disability (Fig. 6) were assessed over 6 hours period (Figs. 5 A and 6A) or cumulated across the 0-2 hours period of peak-effect (Figs. 5B and 6B). Data are median (Tables 3 and 4) with individual values (Figs. 5 and 6). N=8 for all treatment groups. */**/*** represents P<0.05, P<0.01 or P<0.001 cf. vehicle-treatment. 2- way RM ANOVA (Tables 3 and 4) with Holm-Sidak's test or Friedman test with DUNN'S test (Figs. 5 and 6).
[00241] Data from study 1: Pridopidine produced a significant and dose dependent reduction in dyskinesia evoked by L-DOPA in study 1 (Figure 7A-B). Figure 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).
[00242] Pridopidine did not reduce the beneficial anti-parkinsonism effect of L-DOPA (Fig 8A-B). Fig 8 A examining the whole 6 hr time course and Fig 8B is a bar graph showing individual animals at 0-2 hours after L-DOPA.
[00243] Data are medians (Figures 7A, 8A) with individual values (Figures 7B, 8B). N=8 for all treatment groups. * / ** / *** represents P<0.05, P<0.01 or P<0.001 cf. vehicle-treatment, 2-way ANOVA with Holm-Sidak PHT (Figure 7A, and 8 A), Friedman’s test with Dunn’s PHT (Figures 7B, 8B,). For reference (but not included in statistical analyses,▲ describes data in response to vehicle-vehicle treatment).
Effects of pridopidine on L-DOPA-induced dystonia and chorea
[00244] Pridopidine produced a significant and dose-dependent reduction in levels of L- DOPA-induced dystonia evoked by LDh. Examining the whole 6 hr time-course revealed a significant effect of combination treatment (F (3, 28) = 7.017, P=0.0012) but not time (F (5, 140) = 0, P>0.9999) or the interaction of treatment and time (F (15, 140) = 0.9735, P=0.4863) on levels of dystonia (2-way, RM-ANOVA, Fig. 9A, Table 5).
Table 5: Effect of escalating doses of pridopidine on L-DOPA induced Dystonia
Figure imgf000055_0001
ns: not significant. */**/*** represents P<0.05, P<0.01 or P<0.001 cf. vehicle-treatment. 2-way RM ANOVA with Holm-Sidak's test or Friedman test with DUNN'S test
[00245] Comparing to LDh-vehicle treatment revealed a significant decrease in dystonia during the first hour (20 and 30 mg/kg) and second and third hours (30 mg/kg) after start of observation in response to LDh when combined with pridopidine, with median levels remaining between moderate and marked (20 mg/kg) or mild to moderate (30 mg/kg) (all P<0.05). Assessing levels of dystonia cumulated over the 0-2 h period revealed a significant effect of pridopidine combination treatment (0-2 h; Friedman Statistic (FS) = 11.88, P=0.0078, Fig. 9B) on levels of dystonia evoked by LDh administration. Median levels of dystonia in animals treated with LDh combined with high-dose pridopidine (30 mg/kg) were reduced (by 72%) compared to that seen following LDh-vehicle such that median levels of dyskinesia were below mild (non-disabling) (P<0.01).
[00246] Pridopidine significantly reduced L-DOPA induced dystonia (study 1), in a dose dependent manner. Figure 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.
[00247] Pridopidine significantly reduced L-DOPA induced chorea. Figure 9D) (study 1) 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.
Effects of pridopidine on duration and quality of on-time
[00248] Pridopidine produced no change in the total duration of on-time but improved the quality of on-time associated with LDh (Fig. 10;“bad” on time black,“good” on time white, y axis = minutes). Thus, 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). Specifically, assessed over the six -hour period of observation while there was no effect of treatment (F (3, 21) = 1.659, P=0.2062), there was significant effect of on-time subtype (total, good or bad; F (2, 14) = 18.29, P=0.0001) and the interaction of treatment and subtype (F (6, 42) = 2.887, P=0.0190) on duration and quality of on-time (2-way, RM-ANOVA, Fig. 10). Post-hoc Holm-Sidak’s analysis revealed no difference in either duration of total on-time or proportion of on-time that was of‘good’ quality in response to LDh when combined with any dose of pridopidine compared to that observed following LDh-vehicle treatment. By contrast, pridopidine produced a significant reduction in‘bad’ quality on-time with a decrease of 60% evident following administration of the 30 mg/kg dose compared to vehicle treatment (66 min cf 168 min respectively, P<0.01).
Discussion
[00249] 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. Although those doses of L-DOPA administered in clinical settings are generally lower, on a mg/kg basis than those administered to the MPTP-lesioned macaque even corrected for human equivalent dosing (HED), we have shown that they deliver equivalent plasma pharmacokinetic profiles to those achieved with clinically relevant L-DOPA doses as given to PD patients (Dizdar 1999; Huot 2012).
[00250] The cellular target of pridopidine was evaluated in various in vitro binding assays. Pridopidine binds with highest affinity to the Sigma- 1 receptor (S IR, binding IC50 ~ lOOnM), approximately 100 fold higher affinity compared to an earlier described target, the Dopamine D2R (IC50 ~ 10 mM) and to several other central nervous system (CNS) receptor targets, including, serotonin (5 -hydroxy tryptamine [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.
[00251] 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 mM, respectively) and AUCO-24 values of 1214, 4905, 8207 and 22987 ng*h/ml (corresponding to 4.3, 17.5, 29.2 and 81.8 h*pM) Receptor occupancy was estimated using (i) known binding affinities of pridopidine to human and rodent S IR and D2R in vitro (ii) in vivo PET imaging in rats, NHP and human, and (iii) pharmacokinetic PK profiling in the different species. Plasma exposures observed following the low, ineffective doses (7 mg/kg and 15 mg/kg (study 1), and 20 mg/kg which exhibited a trend for an effect but not significant in study 2), is expected to be associated with full S IR occupancy >80% but with negligible engagement of low affinity dopamine receptors, with, occupancy about 10%. Plasma exposures following the high, effective dose (30 mg/kg (or 20 mg/kg in study 1)) is expected to saturate the S IR (> 80% occupancy) and have a higher (about 40%) occupancy of the low affinity dopamine receptors.
[00252] In MPTP-lesioned NHPs, high-dose pridopidine produced a significant and meaningful decrease in LID without compromising the anti-parkinsonian benefit of L-DOPA. A complex pharmacology may underlie the effectiveness of pridopidine against LID.
[00253] Contrary to what was observed in HD, administration of pridopidine at low doses was ineffective against LID whereas high doses of pridopidine exhibited beneficial effects in reducing in LID in a PD NHP model. In HD, by contrast, pridopidine is beneficial at low doses but no benefit is observed at high doses. These studies provide data to support the use of high- dose pridopidine for the treatment of dyskinesia and DIMD, including LID in PD patients.
EXAMPLE 4
Therapy for treating LID in PD patients
[00254] Periodically orally administering of pridopidine (greater or equal to 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.
[00255] The therapy provides efficacy in treating the patient without undue adverse side effects or affecting the safety of the treatment:
1. The therapy is effective in improving symptoms of dyskinesia.
2. The therapy does not produce any significant side effects such as sedation and depression.
3. The therapy does not affect the anti -parkinsonian benefit of L-DOPA.
4. The therapy improves the bad quality on-time evoked by levodopa. EXAMPLE 5
Add-on therapy for treating LID in PD patients
[00256] Periodically orally administering of pridopidine (for example 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 90 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 500 mg/day) as an add-on therapy for a human subject afflicted with LID who is already receiving amantadine provides a clinically meaningful advantage and is more effective (provides at least an additive effect or more than an additive effect) in treating the patient than when administering pridopidine alone (at the same dose).
[00257] 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:
1. The add-on therapy is effective (provides at least an additive effect or more than an additive effect) in improving symptoms of dyskinesia.
2. The add-on therapy does not produce any significant side effects such as sedation and depression.
EXAMPLE 6
[00258] Therapy for treating DIMD by administering pridopidine Periodically orally administering of pridopidine (for example for example 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 90 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 400 mg/day, 500 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.
[00259] The therapy also provides efficacy in treating the patient without undue adverse side effects or affecting the safety of the treatment:
1. 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.
2. The therapy does not produce any significant side effects such as sedation and depression. EXAMPLE 7
Therapy for treating DIMD by administering combination of pridopidine and an
additional therapeutic agent
[00260] Periodically orally administering of pridopidine (for example 10 mg/day, 15 mg/day, 20 mg/day, 45 mg/day, 90 mg/day, 180 mg/day, 200 mg/day, 225 mg/day, 250 mg/day, 300 mg/day, 350 mg/day, 400 mg/day or 500 mg/day) and one or more additional therapeutic agent 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.
[00261] The additional therapeutic agent includes Amantadine, Dipraglurant (ADX48621), Foliglurax, IRL790, Eltoprazine, Buspirone, Levetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof.
[00262] The therapy provides efficacy in treating the patient without undue adverse side effects or affecting the safety of the treatment:
1. The therapy is effective in improving symptoms of dyskinesia.
2. The therapy does not produce any significant side effects such as sedation and depression.
3. The therapy does not affect the anti -parkinsonian benefit of L-DOPA.
4. The therapy improves the bad quality on-time evoked by levodopa.
EXAMPLE 8
Combination therapy of pridopidine with amantadine (AMT) in reducing AIMs in PD patients
[00263] The aims of this study were to assess the benefits of pridopidine as an add-on to amantadine (AMT) and, in doing so, define whether combination of AMT with pridopidine, will enhance the anti-dyskinetic benefit achieved by either drug given alone at the same dose, in response to high-dose L-DOPA.
[00264] The first Experiment in this study assayed a dose-dependent response of pridopidine on L-DOPA induced AIMS and net contraversive rotations. The effects of acute administration of vehiclei or 4 doses of pridopidine (3, 15, 30 or 60 mg/kg) given in combination with LDh were determined via assessment of AIMs and rotational behaviour prior to, and every twenty minutes for 3 h after administration of L-DOPA for a total of 10 assessments (Figs 11A- 11D to 13A-13C).
[00265] The second Experiment assessed the anti-dyskinetic benefit of a single dose of pridopidine (15 mg/kg, PO) previously shown to produce subthreshold results, given alone and in combination with two suboptimal doses of AMT (5 and 10 mg/kg, SC) (Figs. 14A-14D) that were characterized previously to produce subthreshold (5 mg/kg) and an approximate 50% reduction (10 mg/kg) in AIMs and net contraversive rotations.
Experimental:
[00266] The anti-dyskinetic activity of acute administration of each treatment combination on L-DOPA-induced abnormal involuntary movements (AIMs) was assessed in the 6- hydroxydopamine (6-OHDA)-lesioned rat model of PD. AIMs represent a rodent correlate of LID.
[00267] Twenty female Sprague Dawley rats received unilateral injections of 6-OHDA into the medial forebrain bundle. From these animals, those showing a robust rotational response following administration of apomorphine (a minimum of N=10) were selected for subsequent testing.
[00268] These animals then received once-daily administration of L-DOPA (10 mg/kg, IP) for a period of 3 weeks until stable and robust AIMs were evoked, i.e. a model of advanced PD when motor complications have become established.
[00269] The power calculation was based upon defining a change in levels of AIMs during the peak-effect period (20-120 min post L-DOPA administration). This endpoint was chosen as it is potentially the most variable. A minimal effect size of 25% was defined, t chosen as it represents the smallest definable change, a 1 -point change on the basic 4-point rating that comprises the cumulative AIMs score.
[00270] Following completion of baseline behavioral testing, the effects of acute administration of six treatment combinations were assessed. The treatment combinations are detailed in the following Table 6.
Table 6: Treatment combinations
Figure imgf000061_0001
[00271] Treatments 1-3 from Table 6:
[00272] For Treatments 1-3, high-dose L-DOPA (LDh; 6 mg/kg) were combined with vehiclel (that for pridopidine) and either vehicle2 (that for AMT) or AMT (5 and 10 mg/kg, SC).
[00273] Treatments 4-6 from Table 6 (Figs. 14A-14D):
[00274] For Treatments 4-6, LDh (6 mg/kg) was combined with pridopidine (15 mg/kg,
PO) and either vehicle2 (that for AMT) or AMT (5 and 10 mg/kg, SC). LDh 6 mg/kg was pre defined as a dose that produces maximal levels of anti -parkinsonian benefit and rotation, but which is associated with severe / disabling levels of AIMs.
[00275] Vehiclel (or pridopidine) and vehicle2 (or AMT) were administered 1 h prior to LDh and start of behavioural observations (rotational behaviour and AIMs, assessed for a period of 3 hours).
[00276] The order of treatments within the Study and within each animal was randomised using an incomplete Latin Square-type design.
Methods:
[00277] A total of 20 animals received unilateral lesions of the right nigrostriatal pathway via injection of 12.5 pg of 6-hydroxy dopamine (6-OHDA) into a single site in the medial forebrain bundle. Animals left untreated for 2 weeks to allow the lesion to develop and stabilize prior to start of behavioral assessments.
[00278] Two weeks following stereotaxic surgery, to gauge the extent of the 6-OHDA- induced lesion, all animals underwent assessment of contraversive rotational behavior observed in response to administration of apomorphine. Thus, animals received acute administration of apomorphine HC1 (0.05 mg/kg of the freebase corrected weight, SC) and rotational behavior was assessed continuously for 90 min. All animals (with a required minimum of N=12) bearing a robust lesion (defined as producing a total of more than 50 net contraversive rotations in the first hour immediately following administration of apomorphine) were included for subsequent testing.
[00279] Following completion of animal selection assessments, all animals (minimum of 10) that reached the inclusion criteria were administered L-DOPA, once daily, for 21 days (Weeks 4-6).
AIMs and rotational behavior were assessed prior to, and every twenty minutes for 3 h after treatment administration (10 assessments). The 10 animals displaying the highest levels of AIMs (a minimum score of 3 for at least 3 consecutive periods of assessment) were advanced to the next study component. (Figs. 11A-D, Figs 12A-12C and Figs 13A-13C).
Behavioural assessments
Assessment of rotational behaviour
[00280] Commencing immediately following administration of apomorphine or L-DOPA, rotational behavior was assessed using an automated rotometer apparatus (Med Associates, USA) for a period of 3 h.
Abnormal involuntary movements (AIMs) testing
[00281] Animals assessed for AIMs during rotational observations. Each rat was observed for 1 min prior to treatment and every 20 min for a 3 h time period following treatment. Three subtypes of AIMs were assessed including:
• · Limb (Li) - Random uncontrollable movements of forelimb contralateral to the lesion
• · Orolingual (01) - Excess chewing and jaw movements with protrusion of the tongue
• Axial (Ax) - dystonic postures or choreiform twisting of the neck and upper body towards the contralateral side
[00282] For each subtype, the duration of AIMs was scored between 1 and 4 as described below:
1 = Present for less than 30 seconds
2 = Present for more than 30 seconds 3 = Present throughout the minute but suppressed by external stimuli
4 = Present throughout the minute but not suppressible by external stimuli
[00283] A score was given that denotes the maximum or highest score obtained across the observation period both for each of the subtypes individually and across all combined.
[00284] For each point of observation (1 min every 20 min) each of the three ALO-AIMs subscores (Axial, limb and orolingual) are scored from 0-4 and the resulting data summed to give a max possible score for that timepoint of 12 (max of y-axis for time-course). In categories the scores are as follows:
0 - absent
3 - mild
6 - moderate
9 - marked
12 - severe
[00285] For any graphs cumulated over the 20-120 min period this takes in a total of 5 time- points (20-40, 40-60, 60-80, 80-100 and 100-120). The y-axis max score is 60 with categories for each score as follows.
0 - absent
15 - mild
30 - moderate
45 - marked
60 - severe
Results:
AIMs levels following treatment with pridopidine alone
[00286] Figures 11A-11D present change in levels of AIMs following treatment with pridopidine at different doses, as described above. Female 6-OHDA lesioned rats treated with L- DOPA once-daily for a period of 3 weeks as a model of advanced PD when motor complications have become established, followed by treatment of pridopidine at 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg doses during 3hrs. The AIMs level was measured. Most robust effects were observed with 30 and 60 mg/kg. Figure 11A presents change in levels of AIMs during 3 hours measured every 20 minutes at different doses of pridopidine 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg vs. vehicle. Figure 11B presents a total of 20-120 min totals bars of results presented in Figure 11A. The results of Figures 11A and 1 IB are also presented in Table 7. [00287] Table 7: AIMs levels following treatment of pridopidine
Figure imgf000064_0001
[00288] Figure 11C presents net contraversive rotations of the rats during 3 hours measured every
20 minutes at different doses of pridopidine 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg vs. vehicle. Figure 11D presents a total of 20-120 min totals bars of results presented in Figure 11C. The results of Figures 11 A and 1 IB are also presented in Table 8.
[00289] Table 8: Net contraversive rotations following treatment of pridopidine
Figure imgf000064_0002
[00290] Figures 12A-12C present AIMs subscores (time-courses) per 20 minutes of Limb, Axial and Orolingual following treatment with pridopidine at different doses as described above. Female 6-OHDAlesioned rats treated with L-DOPA followed by treatment of pridopidine at 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg doses during 3hrs. Figure 12A presents the Limb results as presented also in Table 9: Table 9: Limb results following treatment of pridopidine
Figure imgf000065_0001
[00291] Figure 12B presents the Axial results, as presented also in Table 10:
Table 10: Axial results following treatment of pridopidine
Figure imgf000065_0002
[00292] Figure 12C presents the Orolingual results, as presented also in Table 11:
Table 11: Orolingual results following treatment of pridopidine
Figure imgf000065_0003
* refers to p<0.05, ** refers to p<0.01 and *** refers to p<0.001 . ns=no signal.
[00293] Figures 13A-13C present AIMs subscores (20-120 min totals) bars (Limb, Axial and Orolingual) following treatment with pridopidine at different doses as presented in Figures
12A to 12C and described above. Female 6-OHDA lesioned rats treated with L-DOPA followed by treatment of pridopidine at 3 mg/kg, 15 mg/kg, 30 mg/kg and 60 mg/kg doses during 3hrs. Figure 13A presents the Limb results. Figure 13B presents the Axial results. Figure 13C presents the Orolingual results.
AIMs levels following treatment with pridopidine and AMT demonstrating synergistic effect
[00294] As discussed above the effects of six acute treatment combinations in a cohort of 6-OHDA-lesioned rats with established L-DOPA-induced AIMs were assessed. Treatments included:
• Vehicle, or,
• pridopidine (15 mg/kg; dose selected as being sub-threshold for anti-AIMs effect from but which did reduce net contraversive (CV) rotations)
in combination with either
• Vehicle, or,
• AMT 5 mg/kg, or,
• AMT 10 mg/kg.
[00295] LDh; 6 mg/kg were combined with vehicle 1 (that for pridopidine) and either vehicle2 (that for AMT) or AMT (5 and 10 mg/kg, SC).
[00296] The combination of 15mg/kg of pridopidine with 5 mg/kg and 10 mg/kg was effective to reduce AIMs to mild levels (Figs. 14A and 14B) as presented in Table 12:
Table 12: AIMs levels following treatment of pridopidine and AMT
Figure imgf000066_0001
* refers to p<0.05, ** refers to p<0.01 and *** refers to p<0.001 . ns=no signal.
[00297] In addition, the net contraversive rotations were decreased when the higher dose of AMT with 15 mg/kg pridopidine were administered (Figs. 14C and 14D) as presented in Table 13: Table 13: Net contraversive rotations following treatment of pridopidine and AMT
Figure imgf000067_0001
* refers to p<0.05, ** refers to p<0.01 and *** refers to p<0.001 . ns=no signal.
[00298] Pridopidine / AMT combination produces a clear synergism such that levels of AIMs are robustly reduced to an extent that far exceeds that achievable by each agent given alone.
[00299] The pridopidine / AMT combination also shows a pronounced decrease in net contraversive rotations which is typical of an agent with effective anti- AIMs activity.
REFERENCES
[001] “Huntexil®’ The NeurosSearch website, retrieved September 24, 2012, http://neurosearch.com/Default.aspx?ID=8172.
[002] Amantadine PDR 2017 Amantadine hydrochloride - Dmg Summary, PDR
(Prescribes’ Digital Reference), http://www.pdr.net/drug-summary/Amantadine-Hydrochloride- Tablets-amantadine-hydrochloride-2441 and http://www.pdr.net/drug-summary/Amantadine- Hydrochloride-Capsules-amantadine-hydrochloride-1475 accessed September 7, 2017
[003] Bargiotas P. and Konitsiotis S. 2013. Levodopa-induced dyskinesias in Parkinson’s disease: emerging treatments. Neuropsychiatric Disease and Treatment. 9: 1605-1617
[004] Brod et al. 2000 Combination therapy with glatiramer acetate (copolymer- 1) and a type I interferon (IFN-a) does not improve experimental autoimmune encephalomyelitis. Annals of Neurology, 47:127-131.
[005] Brust et al. 2014. Molecular Imaging of sΐ Receptors In Vivo: Current Status and
Perspectives. Curr. Med. Chem. 21, 35-69.
[006] CSID:25948790, www.chemspider.com/Chemical-Structure.25948790.html
(accessed 23:27, Jul 15, 2016).
[007] CSID:7971505, www.chemspider.com/Chemical-Structure.7971505.html
(accessed 23:33, Jul 15, 2016).
[008] Cubo et al.2001. Early morning off-medication dyskinesias, dystonia, and choreic subtypes. Arch. Neurol. 58(9): 1379-1382.
[009] Daneault, J-F. 2013. Drug-induced dyskinesia in Parkinson’s disease. Should success in clinical management be a function of improvement of motor repertoire rather than amplitude of dyskinesia? BMC Medicine, 11:76.
[0010] Dizdar, N., et al., 1999. Human pharmacokinetics of L-3,4-dihydroxyphenylalanine studied with microdialysis. Clin Chem 45, 1813-1820.
[0011] Ecdeu, GW. 1976. Abnormal Involuntary Movement Scale (AIMS) Assessment Manual for Psychopharmacology: Revised (DHEW publication number ADM 76-338). Rockville, MD, US Department of Health, Education and Welfare, Public Health Service, Alcohol, Drug Abuse and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs, 1976: 534-7.
[0012] Gerber PE, Lynd LD. 1998. Selective serotonin-reuptake inhibitor-induced movement disorders. Ann Pharmacother 32: 692-698
[0013] Geva M, et al., 2016. Pridopidine activates neuroprotective pathways impaired in
Huntington Disease. Hum Mol Genet. 25(18):3975-3987. [0014] Goetz et al; 2007. Movement Disorder Society-sponsored revision of the Unified
Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan. Movement Disorders 22(l):41-7.
[0015] Goetz et al; 2008a. Movement Disorder Society-sponsored revision of the Unified
Parkinson's Disease Rating Scale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results. Movement Disorders 23(15):2129-2170.
[0016] Goetz, et al. 2008b. The Unified Dyskinesia Rating Scale: Presentation and
Clinimetric Profile. Movement Disorders 23(16):2398-2403
[0017] Goetz, et al, 2013 Which Dyskinesia Scale Best Detects Treatment Response?
Movement Disorders 28(3):341-346 Hauser, et al. 2004. Parkinson's disease home diary: Further validation and implications for clinical trials. Movement Dis. 19(12): 1409-1413.
[0018] Huot, P, et al, 2012. L-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease. Neuropharmacology 63, 829-836.
[0019] Huot P, et al. 2013 The pharmacology of L-DOPA-induced dyskinesia in Parkinson’s disease. Pharmacol Rev 65: 171-222.
[0020] Jenner, P. 2008. Molecular mechanisms of L-DOPA-induced dyskinesia. Nature Reviews Neuroscience 9: 665-677.
[0021] Johnston, TH et al. and Lee, CS. 2001. "Levodopa-induced dyskinesia:
Mechanisms and management " BCMJ 43(4), 206-9
[0022] Johnston, TH, et al, 2013. TC-8831, a nicotinic acetylcholine receptor agonist, reduces L-DOPA-induced dyskinesia in the MPTP macaque. Neuropharmacology 73, 337-347.
[0023] Kumar, N., et al., 2005 Levodopa-dyskinesia incidence by age of Parkinson's disease onset. Mov Disord. 20, 342-344.
[0024] Manson, A., et al,. 2012 Levodopa-induced-dyskinesias clinical features, incidence, risk factors, management and impact on quality of life. J Parkinsons Dis 2, 189-198 [0025] Marder K, et al. 2000. Rate of functional decline in Huntington’s disease. Neurology 54:452-458.
[0026] Movement Disorder Society Task Force on Rating Scales for Parkinson's Disease. 2003. Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Movement Disorders 18(7):738-50.
[0027] National Research Council Institute for Laboratory Animal, R., Guide for the Care and Use of Laboratory Animals. National Academies Press (US). Copyright 1996 by the National Academy of Sciences. All rights reserved., Washington (DC). [0028] Poewe, W., Mahlknecht, P., 2009. The clinical progression of Parkinson's disease. Parkinsonism Relat Disord.15 Suppl 4, S28-32.
[0029] Ponten H, et al. 2010. In vivo pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol. 644(l-3):88-95.
[0030] Ponten H, et al. 2013. The dopaminergic stabilizer pridopidine decreases expression of L-DOPA-induced locomotor sensitisation in the rat unilateral 6-OHDA model. Eur J Pharmacol. 698(l-3):278-85.
[0031] Sahlholm K, et al. 2013. The dopamine stabilizers ACR16 and (-)-OSU6162 display nanomolar affinities at the s-l receptor. Mol Psychiatry. 18:12-14.
[0032] Sahlholm K, et al. 2015. Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses. Psychopharmacol (Berl) 232(18):3443- 3453.
[0033] Shoulson and Fahn. 1979. Huntington disease: clinical care and evaluation.
Neurology 29:1-3.
[0034] Slifstein et al. 2010. Striatal and Extrastriatal Dopamine Release Measured With
PET and [F-18] Fallypride. Synapse 64(5):350-62.
[0035] Tedroff, J, et al. 2004. A pilot study of the novel dopamine stabiliser ACR16 in advanced Parkinson’s disease. Movement Disorders, Vol. 19, Suppl. 9, P565.
[0036] Thanvi, B. et al. 2007. Levodopa-induced dyskinesia in Parkinson’s disease: clinical features, pathogenesis, prevention and treatment. Postgrad Med J;83:384— 388.
[0037] U.S. Patent No. RE46117 (Sonesson, et al.)
[0038] U.S. Patent No. 7,923,459, issued April 12, 2011 (Gauthier, et al.)
[0039] PCT International Application Publication No. WO2014/205229
[0040] PCT International Application Publication No. WO 2017/015609
[0041] PCT International Application Publication No. WO2018/039477

Claims

What is claimed is:
1. A pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use in treating drug-induced movement disorder (DIMD) in a subject in need thereof.
2. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 1, wherein the one or more additional therapeutic agent is selected from the group consisting of Amantadine, Dipraglurant (ADX48621), Foliglurax, IRL790, Eltoprazine, Buspirone, Levetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof.
3. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 1 or claim 2, wherein the DIMD comprises drug-induced dyskinesia.
4. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 3, wherein the dyskinesia is levodopa-induced dyskinesia (LID).
5. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-4, wherein the subject is afflicted with Parkinson’s disease.
6. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-4, wherein the subject is afflicted with parkinsonism other than Parkinson’s disease.
7. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-6, wherein the subject is concurrently being treated with levodopa.
8. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 7, wherein the pridopidine and the one or more additional therapeutic agents are administered simultaneously with the levodopa.
9. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 7, wherein the pridopidine and the one or more additional therapeutic agents are administered after the levodopa is administered for a period of time.
10. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 7, wherein the levodopa is administered after the pridopidine and the one or more additional therapeutic agents are administered for a period of time.
11. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 9 or claim 10, wherein the period of time is from 10 min to 18 hours.
12. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 9 or claim 10, wherein the period of time is 10 min, 20 min, 30 min, 45 min, 1.0 hour, 2.0 hours, 6.0 hours, or 12 hours or 18 hours.
13. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 7-12, further alleviating or reducing a symptom associated with the levodopa treatment.
14. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 13, wherein the symptom is abnormal movements, myoclonic jerks, irregular movements of extremities, gait, facial grimacing, ataxia, inability to sustain motor act, hand movement or balance, choreiform peak dose dyskinesia, or dystonic peak dose dyskinesia.
15. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 13, wherein the symptom is bad quality on-time evoked by levodopa.
16. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 13-15, wherein the administration of the pridopidine and the one or more additional therapeutic agents improves the symptom of the levodopa induced dyskinesia by at least 10%, by at least 20%, by at least 30% or by at least 50% as measured by MDS-UPDRS or UDysRS.
17. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-16, wherein the pridopidine and the one or more additional therapeutic agents are administered simultaneously or sequentially.
18. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-17, wherein pridopidine and the one or more additional therapeutic agents are administered once daily, twice daily, three times daily, four times daily, or less than once a day.
19. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-18, wherein the pridopidine is in the form of a pridopidine salt.
20. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 19, wherein the pridopidine salt is pridopidine hydrochloride.
21. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of between 10 mg to 500 mg.
22. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of 10 mg once daily, twice daily, three times daily, or four times daily.
23. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of
22.5 mg once daily, twice daily, three times daily, or four times daily.
24. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of 45 mg once daily, twice daily, three times daily, or four times daily.
25. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of
67.5 mg once daily, twice daily, three times daily, or four times daily.
26. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of 75 mg once daily, twice daily, three times daily, or four times daily.
27. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of 100 mg once daily, twice daily, or three times daily.
28. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of
112.5 mg once daily, twice daily, or three times daily.
29. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of 120 mg once daily, twice daily, or three times daily.
30. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of 150 mg once daily, twice daily, or three times daily.
31. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-20, wherein the pridopidine is administered at a dose of 175 mg once daily, twice daily, or three times daily.
32. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claims 1-31, wherein the one or more additional therapeutic agent comprises Amantadine at a dose of between 10 mg to 400 mg.
33. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 32, wherein Amantadine is administered at a dose of 10, 50, 100, 137, 150, 200, 250, 274, 300, 350, or 400 mg.
34. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 32 or claim 33, wherein the Amantadine is administered once daily, twice daily, three times daily, or four times daily.
35. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-31, wherein the one or more additional therapeutic agent comprises Dipraglurant at a dose of between 10 mg to 400 mg.
36. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 35, wherein Dipraglurant is administered at a dose of 50, 100, 200, 250, or 300 mg.
37. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 35 or claim 36, wherein the Dipraglurant is administered once daily, twice daily, three times daily, or four times daily.
38. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claim 1-31, wherein the one or more additional therapeutic agent comprises Foliglurax at a dose of between 10 mg to 50 mg.
39. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 38, wherein Foliglurax is administered at a dose of 10, 20, 30, or 40 mg.
40. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 38 or claim 39, wherein the Foliglurax is administered once daily, twice daily, three times daily, or four times daily.
41. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-31, wherein the one or more additional therapeutic agent comprises IRL790 at a dose of between of 1 mg to 150 mg.
42. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 41, wherein IRL790 is administered at a dose of 10, 18, 50, 100, 120, or 150 mg.
43. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 41 or claim 42, wherein the IRL790 is administered once daily, twice daily, three times daily, or four times daily.
44. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-31, wherein the one or more additional therapeutic agent comprises Eltoprazine at a dose of between of 1 mg to 10 mg.
45. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 44, wherein Eltoprazine is administered at a dose of 1, 2.5, 5.0, 7.5, or 10 mg.
46. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 44 or claim 45, wherein the Eltoprazine is administered once daily, twice daily, three times daily, or four times daily.
47. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-31, wherein the one or more additional therapeutic agent comprises Buspirone at a dose of between of 1 mg to 50 mg.
48. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 47, wherein Buspirone is administered at a dose of 5, 7.5, 10, 15, 20, 25, 30, 35, or 40 mg.
49. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 47 or claims 48, wherein the Buspirone is administered once daily, twice daily, three times daily, or four times daily.
50. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-31, wherein the one or more additional therapeutic agents comprise Levetiracetam at a dose of between of 100 mg to 2000 mg.
51. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 50, wherein Levetiracetam is administered at a dose of 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, or 1500 mg.
52. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 42 or claim 43, wherein the Levetiracetam is administered once daily, twice daily, three times daily, or four times daily.
53. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-31, wherein the one or more additional therapeutic agent comprises Nuedexta (dextromethorphan and Quinidine) at a dose of between 1 mg to 50 mg.
54. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 53, wherein Nuedexta (dextromethorphan and Quinidine) is administered at a dose of 2, 5, 7.5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg.
55. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 53 or claim 54, wherein the Nuedexta (dextromethorphan and Quinidine) is administered once daily, twice daily, three times daily, or four times daily.
56. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of any one of claims 1-31, wherein the weight ratio between the pridopidine and the one or more additional therapeutic agent is from about 1:20 to about 20: 1.
57. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 56, wherein the weight ratio between the pridopidine and the one or more additional therapeutic agent is about 1:20, about 1:15, about 1: 10, about 1:7.5, about 1:5.0, about 1:2.5, about 1:1, about 2.5: 1, about 5: 1, about 7.5: 1, about 10:1, about 15: 1 or about 20: 1.
58. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 1, wherein 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.
59. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 1, wherein the DIMD is selected from parkinsonism, tardive dyskinesia, chorea, dystonia, tremor, akathisia, athetosis, myoclonus or tics.
60. The pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent for use of claim 59, wherein the DIMD is Tardive dyskinesia or drug-induced dystonia.
61. A method of treating drug-induced movement disorder (DIMD) in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of pridopidine and one or more additional therapeutic agent.
62. The method of claim 61, wherein the one or more additional therapeutic agent is selected from the group consisting of Amantadine, Dipraglurant (ADX48621), Foliglurax, IRL790, Eltoprazine, Buspirone, Levetiracetam, and Nuedexta (dextromethorphan/Quinidine), or a combination thereof.
PCT/IL2019/051313 2017-09-08 2019-11-28 Combination of pridopidine and an additional therapeutic agent for treating drug induced dyskinesia WO2020110128A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US17/315,667 US12036213B2 (en) 2017-09-08 2021-05-10 Pridopidine for treating drug induced dyskinesias

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862772814P 2018-11-29 2018-11-29
US62/772,814 2018-11-29

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US16/377,577 Continuation US20190231768A1 (en) 2017-09-08 2019-04-08 Pridopidine for treating drug induced dyskinesias

Related Child Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2018/048920 Continuation-In-Part WO2019050775A1 (en) 2017-09-08 2018-08-30 Pridopidine for treating drug induced dyskinesias
US17/315,667 Continuation-In-Part US12036213B2 (en) 2017-09-08 2021-05-10 Pridopidine for treating drug induced dyskinesias

Publications (1)

Publication Number Publication Date
WO2020110128A1 true WO2020110128A1 (en) 2020-06-04

Family

ID=70853319

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2019/051313 WO2020110128A1 (en) 2017-09-08 2019-11-28 Combination of pridopidine and an additional therapeutic agent for treating drug induced dyskinesia

Country Status (1)

Country Link
WO (1) WO2020110128A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022101227A1 (en) 2020-11-10 2022-05-19 Integrative Research Laboratories Sweden Ab [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine (mesdopetam) for use in the prevention or reduction of sensitization to a pharmaceutical drug for parkinson's disease, in particular l-dopa induced dyskinesias

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013152105A1 (en) * 2012-04-04 2013-10-10 IVAX International GmbH Pharmaceutical compositions for combination therapy
US20130331399A1 (en) * 2012-06-11 2013-12-12 Psychogenics, Inc. Treatment of Motor and Movement Disorder Side Effects Associated with Parkinson's Disease Treatments
US20140088145A1 (en) * 2012-09-27 2014-03-27 Teva Pharmaceutical Industries, Ltd. Combination of rasagiline and pridopidine for treating neurodegenerative disorders, in particular huntington's disease

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013152105A1 (en) * 2012-04-04 2013-10-10 IVAX International GmbH Pharmaceutical compositions for combination therapy
US20130331399A1 (en) * 2012-06-11 2013-12-12 Psychogenics, Inc. Treatment of Motor and Movement Disorder Side Effects Associated with Parkinson's Disease Treatments
US20140088145A1 (en) * 2012-09-27 2014-03-27 Teva Pharmaceutical Industries, Ltd. Combination of rasagiline and pridopidine for treating neurodegenerative disorders, in particular huntington's disease

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Efficacy and Tolerability of IRL790 in Parkinson's Disease Dyskinesia-clinical trial NCT03368170", CLINICALTRIALS.GOV, 20 June 2018 (2018-06-20), pages 1 - 9, XP055712876, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/history/NCT03368170/V_10=View#StudyPageTop> *
BUSPARK: "Buspirone Treatment of Iatrogenic Dyskinesias in Advanced Parkinson Disease", CLINICALTRIALS.GOV IDENTIFIER: NCT02617017, 27 February 2018 (2018-02-27), pages 1 - 7, XP055712858, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/NCT02617017> *
EF. BRIGHAM ET AL.: "Pharmacokinetic/Pharmaodynamic Correlation Analysis of Amantadine for Levodopa-Induced Dyskinesia", J PHARMACOL EXP THER., vol. 367, no. 2, 1 November 2018 (2018-11-01), pages 373 - 381, XP055712764 *
F. TISON ET AL.: "A Phase 2A Trial of the Novel mGluR5-Negative Allosteric Modulator Dipraglurant for Levodopa-Induced Dyskinesia in Parkinson's Disease", MOV DISORD, vol. 31, no. 9, 23 May 2016 (2016-05-23), pages 1373 - 1380, XP055712765 *
P. INACIO: "Lundbeck Acquires Rights to Develop Foliglurax Therapy Candidate to Treat Parkinson's", 21 March 2018 (2018-03-21), Retrieved from the Internet <URL:https://parkinsonsnewstoday.coni/2018/03/21/lundbeck-acquires-rights-develop-parkinsons-disease-therapy-candidate-foliglurax> *
SH FOX ET AL.: "Trial of dextromethorphan/quinidine to treat levodopa-induced dyskinesia in Parkinson's disease", MOV DISORD, vol. 32, no. 6, 30 March 2017 (2017-03-30), pages 893 - 903, XP055712871 *
SW WOODS ET AL.: "Effects of levetiracetam on tardive dyskinesia: a randomized, double-blind, placebo-controlled study", J CLIN PSYCHIATRY, vol. 69, no. 4, 30 April 2008 (2008-04-30), pages 546 - 554 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022101227A1 (en) 2020-11-10 2022-05-19 Integrative Research Laboratories Sweden Ab [2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine (mesdopetam) for use in the prevention or reduction of sensitization to a pharmaceutical drug for parkinson's disease, in particular l-dopa induced dyskinesias

Similar Documents

Publication Publication Date Title
Baldessarini et al. Pharmacotherapy of psychosis and mania
CA2500662A1 (en) Dosage escalation and divided daily dose of anti-depressants to treat neurological disorders
US11000519B2 (en) Pridopidine for treating drug induced dyskinesias
MX2015003812A (en) Combination of rasagiline and pridopidine for treating neurodegenerative disorders, in particular huntington&#39;s disease.
US20220023316A1 (en) Methods for the treatment of depression
EP2624821B1 (en) Combination therapy for the treatment of depression and other non-infectious diseases
US20210353559A1 (en) Composition and method for treating neurological disease
JP2023523569A (en) Methods of treating neurological and psychiatric disorders
CN107949379A (en) The therapeutical uses of 4 chloro kynurenins of L
JP2017519827A (en) Use of buspirone metabolites
US10500170B2 (en) Composition and method for treating neurological disease
US20210353558A1 (en) Composition and method for treating neurological disease
AU2007259256A1 (en) Combination preparations comprising bifeprunox and L-DOPA
WO2020110128A1 (en) Combination of pridopidine and an additional therapeutic agent for treating drug induced dyskinesia
US20240197756A1 (en) Methods of treatment with neuroactive steroids
US12036213B2 (en) Pridopidine for treating drug induced dyskinesias
WO2024107681A1 (en) Methods of switching neuropsychiatric medications using ulotaront
WO2012072665A1 (en) Compositions comprising pipamperone and serotonin antagonist reuptake inhibitors
MX2008016226A (en) Combination preparations comprising bifeprunox and l-dopa.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19888783

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19888783

Country of ref document: EP

Kind code of ref document: A1