WO2023112024A1 - Méthode de traitement de la maladie de parkinson - Google Patents

Méthode de traitement de la maladie de parkinson Download PDF

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WO2023112024A1
WO2023112024A1 PCT/IL2022/051312 IL2022051312W WO2023112024A1 WO 2023112024 A1 WO2023112024 A1 WO 2023112024A1 IL 2022051312 W IL2022051312 W IL 2022051312W WO 2023112024 A1 WO2023112024 A1 WO 2023112024A1
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pharmaceutically
pramipexole
acceptable salt
fixed dose
subject
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PCT/IL2022/051312
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English (en)
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Sheila Oren
Irit AISH
Pninit Litman
Hadas FRIEDMAN
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Pharma Two B Ltd.
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Publication of WO2023112024A1 publication Critical patent/WO2023112024A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings

Definitions

  • Parkinson’s disease is the fastest growing neurological disorder across the globe. In 2016, it was estimated that approximately 6.1 million people are living with the disease. The life-time risk of PD is estimated as high as one in fifteen. A rapid increase in prevalence is not solely due to an aging population, but also due to increasing life expectancy and thus longer disease durations than in previous years. While the prevalence of PD increases steadily with age, almost a quarter of those affected had onset before the age of 65 years old, with the implication that these patients can be expected to live for many years with the disease.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to said subject a pharmaceutical composition comprising a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the dose of pramipexole or a pharmaceutically-acceptable salt thereof is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof, and wherein, if excessive daytime sleepiness is measured in said subject, then a reduced excessive daytime sleepiness is observed in said subject relative to a control subject administered pramipexole monotherapy.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to said subject a pharmaceutical composition comprising a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the dose of pramipexole or a pharmaceutically-acceptable salt thereof is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof, and wherein, if excessive daytime sleepiness is measured in said subject by an Epworth Sleepiness Scale (ESS) score, then a reduced ESS score is observed in said subject relative to a control subject administered pramipexole monotherapy.
  • ESS Epworth Sleepiness Scale
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to said subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically - acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically - acceptable salt thereof, wherein the dose of pramipexole or a pharmaceutically-acceptable salt thereof is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof, and wherein the fixed dose combination effectuates a reduction in excessive sleepiness in said subject relative to a control subject administered pramipexole monotherapy.
  • a method of treating early-stage Parkinson’s disease in a subject in need thereof comprising administering to said subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the dose of pramipexole or a pharmaceutically-acceptable salt thereof is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof, and wherein the fixed dose combination effectuates a reduction in excessive sleepiness in said subject compared to a control subject administered pramipexole monotherapy.
  • a method of reducing, avoiding, diminishing, treating or ameliorating excessive daytime sleepiness in a human subject having Parkinson’s disease, or who is receiving a treatment regimen for Parkinson’s disease comprising a dopamine agonist or a dopaminergic agent, comprising administering to said subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically- acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically- acceptable salt thereof, wherein the dose of pramipexole or a pharmaceutically-acceptable salt thereof is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein, if treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, Impulsive Compulsive Disorder (ICD), constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder are detected or measured in the subject, then reduced treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder are detected or measured in the subject relative to a control subject administered pramipexole monotherapy.
  • TEAEs treatment-
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically - acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically - acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in treatment- emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in the relative to a control subject administered pramipexole monotherapy.
  • TEAEs treatment- emergent adverse events
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically - acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically - acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in treatment- emergent adverse events (TEAEs), including one or more of constipation, dizziness, hallucination, oedema, somnolence, sleep disorder, vomiting, hallucinations gustatory, hallucination visual, hallucinations auditory, gambling disorder, compulsive shopping, obsessive thoughts, obsessive- compulsive, impulsive behavior, impulsive-control disorder.
  • TEAEs treatment- emergent adverse events
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically - acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically - acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in treatment- emergent adverse events (TEAEs), including one or more of nausea, vomiting, diarrhea, constipation, abdominal pain upper, abdominal discomfort, gastritis, dyspepsia, gastroesophageal reflux disease, flatulence.
  • TEAEs treatment- emergent adverse events
  • a method of treating early stage Parkinson’s disease in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in the treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in said subject compared to a control subject administered pramipexole monotherapy.
  • TEAEs treatment-emergent adverse events
  • a method of reducing, avoiding, diminishing, treating or ameliorating treatment-emergent adverse events including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder, vomiting, hallucinations gustatory, hallucination visual, hallucinations auditory, gambling disorder, compulsive shopping, obsessive thoughts, obsessive-compulsive, impulsive behavior, impulsive-control disorder in a human subject having Parkinson’s disease, or who is receiving a treatment regimen for Parkinson’s disease, the treatment regimen comprising a dopamine agonist or a dopaminergic agent, comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof.
  • TEAEs treatment-emergent adverse events
  • a method of reducing, avoiding, diminishing, treating or ameliorating treatment-emergent adverse events including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder, , , vomiting, hallucinations gustatory, hallucination visual, hallucinations auditory, gambling disorder, compulsive shopping, obsessive thoughts, obsessive-compulsive, impulsive behavior, impulsive-control disorder in a human subject having Parkinson’s disease, or who is receiving a treatment regimen for Parkinson’s disease, the treatment regimen comprising a dopamine agonist or a dopaminergic agent, comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically- acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically- acceptable salt thereof.
  • TEAEs treatment-emergent adverse events
  • the method results in a decreased severity of treatment-emergent adverse events (TEAEs), including one or more of nausea, vomiting, diarrhea, constipation, abdominal pain upper, abdominal discomfort, gastritis, dyspepsia, gastroesophageal reflux disease, flatulence of the subject over a defined period of time and the decrease in severity is selected from the group consisting of by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%, as measured by one or more medically recognized technique.
  • TEAEs treatment-emergent adverse events
  • the method results in a decreased severity of GI treatment-emergent adverse events (TEAEs), including one or more of nausea, vomiting, diarrhea, constipation, abdominal pain upper, abdominal discomfort, gastritis, dyspepsia, gastroesophageal reflux disease, flatulence of the subject over a defined period of time and the decrease in severity is selected from the group consisting of by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%, as measured by one or more medically recognized technique.
  • TEAEs GI treatment-emergent adverse events
  • Figure 1 shows plasma concentrations of rasagiline and pramipexole during the 72h following single-dose administration of P2B001 (0.6/0.75mg) ( Figure 1 A and Figure IB) or Mirapex ER + Azilect (0.75/1.0mg) ( Figures 1C and Figure IDs) during the 24 h following single-dose administration of P2B001 on day 1 and during the 72 h following the final dose on day 7 for multipledose administration of P2B001.
  • Figure 2 shows change from baseline in Total UPDRS (Parts 1+11+111) scores in the phase 2 clinical trial.
  • Figure 3 shows phase III, double-blind, double-dummy, parallel group study design.
  • Figure 4 shows temporal pattern of dopaminergic treatment-emergent adverse events (TEAEs) as measured in phase III trial, including somnolence, nausea, vomiting, orthostatic hypotension, hallucinations, hallucinations gustatory, hallucination visual, hallucinations auditory, gambling disorder, compulsive shopping, obsessive thoughts, obsessive-compulsive, impulsive behavior, impulsive-control disorder.
  • TEAEs dopaminergic treatment-emergent adverse events
  • Figure 5 shows temporal pattern of GI adverse events as measured in phase III trial including nausea, vomiting, diarrhea, constipation, abdominal pain upper, abdominal discomfort, gastritis, dyspepsia, gastroesophageal reflux disease, flatulence.
  • the choice of first drug is left to clinical judgment depending on the need for symptomatic efficacy in improving motor disability (lowest with MAO-B inhibitors and highest with levodopa) compared with the risks of developing levodopa-induced motor complications and neuropsychiatric and other adverse effects (lowest with MAO-B and highest with dopamine agonists).
  • the recent AAN guidelines prefer levodopa as the initial therapy for most patients with early PD seeking treatment for motor symptoms, with the relatively high risks of daytime somnolence, impulse control disorders (ICDs) and other cognitive and behavioral adverse effects that are associated with conventional dopamine agonist monotherapy being the driving consideration in the risk-benefit assessment.
  • MAO-B inhibitors are well tolerated but only mildly effective as monotherapy and have mainly been used as monotherapy in the most mildly affected patients.
  • EDS Excessive daytime sleepiness
  • PD Parkinson's Disease
  • EDS can occur in the early stages of PD and its incidence increases with disease progression.
  • EDS may be primary to the disease's progression itself or secondary due to the use of pharmacological therapy, such as antidepressants, antihistamines, antipsychotics or sedatives, in particular dopamine agonists.
  • dopamine replacement therapy, levodopa which is the most common treatment for Parkinson's disease, is known to be associated with increasing excessive daytime sleepiness. Accordingly, this disabling condition is probably caused by a combination of the neurodegenerative process affecting most ascending arousal systems in the brain and the effects of dopaminergic drugs.
  • Excessive daytime sleepiness may be assessed with the Epworth Sleepiness Scale (ESS) [Sleep, 1991, 14, 540-545; epworthsleepinessscale.com], which is a self-administered 8-items questionnaire with scores interpreted as follows: 0-5 lower normal daytime sleepiness, 6-10 higher normal daytime sleepiness, 11-12 mild excessive daytime sleepiness, 13-15 moderate daytime sleepiness, 16-24 severe daytime sleepiness.
  • ESS Epworth Sleepiness Scale
  • PD Parkinson's disease
  • PD refers to "early-stage PD”.
  • PD refers to "mid-stage PD”.
  • PD refers to "advanced-stage PD”.
  • Parkinson's disease patient or “patient with Parkinson's disease” refers to a patient diagnosed with Parkinson's disease, for example, as defined herein above. In one embodiment, it refers to a Parkinson's disease patient (e.g. as defined herein) with excessive daytime sleepiness (e.g. as defined herein).
  • dopamine-replacement therapy refers to the principal symptomatic treatment for PD that is based upon administration of either (i) an agent replacing, or increasing the level of, endogenous dopamine (e.g., levodopa (L-DOPA)), or (ii) a dopamine receptor agonist (e.g., apomorphine).
  • an agent replacing, or increasing the level of, endogenous dopamine e.g., levodopa (L-DOPA)
  • a dopamine receptor agonist e.g., apomorphine
  • ICSD- 3 criteria i.e. according to the International Classification of Sleep Disorders-third Ed.: American Academy of Sleep Medicine, 2014
  • ICSD-3 criteria defined for hypersomnia due to a medication or substance, which are incorporated herein by reference, relate to the three diagnostic criteria that need to be met (i.e.
  • the patient has daily periods of irrepressible need to sleep or daytime lapses into sleep
  • the daytime sleepiness occurs as a consequence of current medication or substance use or withdrawal from a wake-promoting medication or substance
  • the symptoms are not better explaineds by another untreated sleep disorder, medical or neurological disorder, or mental disorder.
  • the method of treating of the invention promotes wakefulness.
  • the method results in a decreased severity of the excessive day sleepiness of the subject over a defined period of time and the decrease in severity is selected from the group consisting of by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%, as measured by one or more medically recognized technique.
  • the term "promoting wakefulness”, as used herein, refers to decreasing excessive daytime sleepiness, for example, compared with excessive daytime sleepiness observed without treatment, for example as measured by the Epworth Sleepiness Scale (e.g.
  • the term "for use in promoting wakefulness”, as used herein, is to be understood as “for use in a treatment promoting wakefulness” or “for use in a method of treatment promoting wakefulness”.
  • the term “for a treatment promoting wakefulness”, as used herein, is to be understood as “for a method of treatment promoting wakefulness”.
  • the term “treat”, “treating” or “treatment” in connection to a disease or disorder refers in one embodiment, to ameliorating the PD (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • treat refers to alleviating or ameliorating at least one physical parameter including those, which may not be discernible by the patient.
  • “treat”, “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.
  • the terms “method for the treatment” or “method for treating”, as used herein refer to "method to treat”.
  • the method of treating of the invention treats, reduces, prevents, and/or decreases the hallucinations: (a) the hallucination may comprise a visual, auditory, tactile, gustatory or olfactory hallucination; (b) the method results in a decreased number or severity of hallucinations of the subject; (c) the method may result in a decreased number or severity of hallucinations of the subject and the decrease in number or severity in hallucinations can be defined as a reduction in occurrences or severity of hallucinations selected from the group consisting of by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%; and/or (d) the method may result in the subject being hallucination-free and/or (e) the method results in a decreased severity of hallucinations of
  • Orthostatic hypotension also called postural hypotension is a form of low blood pressure that happens when standing after sitting or lying down. Orthostatic hypotension can cause dizziness or lightheadedness and possibly fainting. Orthostatic hypotension can be mild. Episodes might be brief.
  • the methods of the present disclosure minimize orthostatic hypotension.
  • the method is substantially devoid of orthostatic hypotension.
  • the risk of orthostatic hypotension in the patient is about the same as or similar to placebo.
  • the method results in orthostatic hypotension in less than or equal to 2.7% of patients.
  • the method results in orthostatic hypotension in less than or equal to about 10, 9, 8, 7, 6, 5, 4, 3, 2, 1% of patients.
  • the method results in orthostatic hypotension in a percentage of patients that is no more than placebo.
  • the method results in a decreased severity of orthostatic hypotension of the subject over a defined period of time and the decrease in severity is selected from the group consisting of by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%, as measured by one or more medically recognized technique.
  • patient refers to a subject who is diseased and would benefit from the treatment.
  • yielderly patient refers to a patient sixty-five years of age or older.
  • the term "subject” refers to a mammalian organism, preferably a human being (male or female).
  • a subject is "in need of' a treatment if such subject (patient) would benefit biologically, medically or in quality of life from such treatment.
  • a therapeutically effective amount of a compound of the present invention refers to an amount of a compound of the present invention that will elicit the biological or medical response of a subject, for example, ameliorate symptoms, alleviate conditions, etc. In some embodiments, the efficacy will be achieved with less side effects such as sleepiness, hallucinations and/or orthostatic hypotension.
  • pharmaceutical composition is defined herein to refer to a mixture or solution containing at least one active ingredient or therapeutic agent to be administered to a subject, in order to treat a particular condition (i.e. disease, disorder or condition or at least one of the clinical symptoms thereof) affecting the subject.
  • composition is defined herein to refer to an extended-release composition containing a composition rasagiline and pramipexole or a pharmaceutically acceptable salt thereof to be administered to a subject, in order to treat the PD affecting the subject.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the therapeutic compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the active agent.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and other known to those of ordinary skill in the pharmaceutical sciences.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like
  • organic acids such
  • the salt is mesylate, which is any salt or ester of methanesulfonic acid (CH3SO3H).
  • CH3SO3H methanesulfonic acid
  • the rasagiline is rasagiline mesylate.
  • the pramipexole is pramipexole dihydrochloride monohydrate.
  • the combination is a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein, in some embodiments, the dose of pramipexole or a pharmaceutically-acceptable salt thereof is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises from about 0.1 mg to about 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and from about 0.1 mg to about 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof, wherein, in some embodiments, the dose of pramipexole or a pharmaceutically-acceptable salt thereof is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof. In some embodiments, the fixed dose combination comprises 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination is in a form of a capsule, a tablet, a pill, a dragee, a powder, a granule, an emulsion, a solution, or a suspension.
  • the term "pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 22 nd Ed. Mack Printing Company, 2013, pp. 1049-1070).
  • other dopaminergic agonist or other dopaminergic agent as used herein (e.g. in any of embodiments herein above, or in any of the claims, herein below), refers, for example, to amantadine, selegiline, rasagiline, entacapone, ramelteon, melatonin, zolpidem, eszopiclone, zopiclone, brotizolam, trazodone, doxepin, darifenacin, solifenacin, tolterodine, pregabalin, gabapentin, enacarbil, paroxetine, donepezil, rivastigmine, desipramine, carbamazepine, clonazepam, lorazepam, triazolam, temazepam, flurazepam, ca
  • P2B001 is a combination capsule developed to slowly release pramipexole and rasagiline simultaneously throughout the day. Both components have a large evidence-base supporting their efficacy. Whereas pramipexole provides the stronger symptomatic effect of the two, its use is limited by the development of dose-related adverse events. Therefore, the P2B001 ER-pramipexole component dose is limited in some embodiments to 0.6 mg/day.
  • Pramipexole is a full, nonergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2-iike subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes (Ki’s of 0.5nM vs 3.3-3.9nM, respectively).
  • the ratio of selectivity for D3 over D2 is about 6.5-8, with some evidence of selectivity in functional assays.
  • Affinity to Di receptors is insignificant, being around 200000 times lower than that to D3 receptors.
  • the mechanisms of pramipexole action are not fully elucidated. However, it is known that pramipexole acts on presynaptic as well as on postsynaptic dopamine receptors.
  • pramipexole has a reduced propensity to cause motor complications, which has led to its use (along with other D2 receptor agonists) as a preferred option for initial monotherapy particularly in younger patients who have greater risk to develop dyskinesias in response to levodopa.
  • D2 receptor agonists D2 receptor agonists
  • Rasagiline N-propargyl-l-(R)-aminoindan
  • MAO-B monoamine oxidase type B
  • FAD flavin adenine dinucleotide
  • rasagiline prevents the access of dopamine to MAO-B, thereby inhibiting oxidative deamination to 3,4- dihydroxphenlyacetic acid (DOPAC) and raising the levels of dopamine.
  • MAO-B inhibition with rasagiline also increases the availability of phenylethylamine, which can enhance striatal dopamine release.
  • Striatal dopamine release may also be enhanced by the rasagiline active metabolite, 1 -aminoindan, an effect which is thought to be separate from MAO-B inhibition (although 1 -amino-indan is also a weak MAO-B inhibitor).
  • Both rasagiline and aminoindan contain a propargylamine moiety which have been shown to inhibit apoptosis both in in vitro and in vivo models of PD.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein, if treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, Impulsive Compulsive Disorder (ICD), constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder are detected or measured in the subject, then reduced treatment- emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder are detected or measured in the subject relative to a control subject administered pramipexole monotherapy
  • TEAEs treatment-
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof and both rasagiline and pramipexole are slow released.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in the subject relative to a control subject administered pramipexole monotherapy.
  • TEAEs treatment-emergent adverse events
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof and both rasagiline and pramipexole are slow released.
  • the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.
  • the fixed dose combination comprises pramipexole dihydrochloride monohydrate. In some embodiments, the fixed dose combination comprises rasagiline mesylate.
  • the fixed dose combination comprises from about 0.1 mg to about 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and from about 0.1 mg to about 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 gr of pramipexole dihydrochloride monohydrate based on the mass of pramipexole, and 0.75 mg of rasagiline mesylate based on the mass of rasagiline.
  • the fixed dose combination is in a form of a capsule, a tablet, a pill, a dragee, a powder, a granule, an emulsion, a solution, or a suspension.
  • the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the fixed dose combination provides an extended release of the rasagiline or pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the rasagiline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the administering is once-daily.
  • the fixed dose combination effectuates a reduction in treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in the subject relative to a control subject administered pramipexole monotherapy.
  • TEAEs treatment-emergent adverse events
  • the treating Parkinson’s disease or a symptom thereof is measured by a Unified Parkinson’s Disease Rating Scale (UPDRS), wherein the fixed dose combination is effective at reducing a total UPDRS score in the subject relative to baseline.
  • the fixed dose combination provides superior efficacy at treating Parkinson’s disease or a symptom thereof while reducing treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in the subject compared to a control subject receiving an individual component of the fixed dose combination.
  • TEAEs treatment-emergent adverse events
  • the dose of pramipexole is 0.6 mg or more. In some embodiments, the dose of pramipexole or a pharmaceutically-acceptable salt thereof is about 0.6 mg or from about 1.5 mg to about 4.5 mg.
  • the subject has early stage Parkinson’s disease.
  • a method of treating early stage Parkinson’s disease in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in the treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in the subject compared a control subject administered pramipexole monotherapy.
  • TEAEs treatment-emergent adverse events
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof and both rasagiline and pramipexole are slow released.
  • a method of reducing, avoiding, diminishing, treating or ameliorating treatment-emergent adverse events including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in a human subject having Parkinson’s disease, or who is receiving a treatment regimen for Parkinson’s disease, the treatment regimen comprising a dopamine agonist or a dopaminergic agent, comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof.
  • TEAEs treatment-emergent adverse events
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof and both rasagiline and pramipexole are slow released.
  • the dopamine agonist or dopaminergic agent is one or more of levodopa, amantadine, selegiline, entacapone, ramelteon, melatonin, zolpidem, eszopiclone, zopiclone, brotizolam, trazodone, doxepin, darifenacin, solifenacin, tolterodine, pregabalin, gabapentin, enacarbil, paroxetine, donepezil, rivastigmine, desipramine, carbamazepine, clonazepam, lorazepam, triazolam, temazepam, flurazepam, cabergoline, rotigotine, suvorexant, pergolide, cabergoline, ropinirole, carbidopa, benserazide, clozapine, quetiapine, primavanesr
  • the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.
  • the fixed dose combination comprises pramipexole dihydrochloride monohydrate.
  • the fixed dose combination comprises rasagiline mesylate.
  • the fixed dose combination comprises from about 0.1 mg to about 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and from about 0.1 mg to about 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 gr of pramipexole dihydrochloride monohydrate based on the mass of pramipexole, and 0.75 mg of rasagiline mesylate based on the mass of rasagiline.
  • the fixed dose combination is in a form of a capsule, a tablet, a pill, a dragee, a powder, a granule, an emulsion, a solution, or a suspension.
  • the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the fixed dose combination provides an extended release of the rasagiline or a pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the rasagline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the administering is once-daily.
  • the fixed dose combination effectuates a reduction in treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in the subject relative to a control subject not receiving Parkinson’s disease therapy.
  • TEAEs treatment-emergent adverse events
  • the fixed dose combination effectuates a reduction in treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in the subject relative to a control subject administered pramipexole monotherapy.
  • TEAEs treatment-emergent adverse events
  • the fixed dose combination is effective at treating Parkinson’s disease or a symptom thereof.
  • the fixed dose combination provides superior efficacy at treating Parkinson’s disease or a symptom thereof while reducing hallucinations or orthostatic hypertension in the subject compared to a control subject receiving an individual component of the fixed dose combination.
  • the fixed dose combination provides substantially comparable efficacy at treating Parkinson’s disease or a symptom thereof while reducing treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder in the subject compared to a control subject receiving a treatment regimen comprising pramipexole or a pharmaceutically-acceptable salt thereof.
  • TEAEs treatment-emergent adverse events
  • the method results in a decreased severity of treatment-emergent adverse events (TEAEs), including one or more of orthostatic hypotension, ICD, constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder vomiting, hallucinations, hallucinations gustatory, hallucination visual, hallucinations auditory, gambling disorder, compulsive shopping, obsessive thoughts, obsessive-compulsive, impulsive behavior, impulsive-control disorder of the subject over a defined period of time and the decrease in severity is selected from the group consisting of by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%, as measured by one or more medically recognized technique.
  • TEAEs treatment-emergent adverse events
  • the method results in a decreased severity of GI treatment-emergent adverse events (TEAEs), including one or more of nausea, vomiting, diarrhea, constipation, abdominal pain upper, abdominal discomfort, gastritis, dyspepsia, gastroesophageal reflux disease, flatulence of the subject over a defined period of time and the decrease in severity is selected from the group consisting of by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, and about 100%, as measured by one or more medically recognized technique.
  • TEAEs GI treatment-emergent adverse events
  • the dose of pramipexole is 0.6 mg or more. In some embodiments, the dose of pramipexole or a pharmaceutically-acceptable salt thereof is about 0.6 mg or from about 1.5 mg to about 4.5 mg.
  • the efficacy at treating Parkinson’s disease or a symptom thereof is measured by a Unified Parkinson’s Disease Rating Scale (UPDRS), wherein the fixed dose combination is effective at reducing a total UPDRS score in the subject relative to baseline.
  • UPDRS Unified Parkinson’s Disease Rating Scale
  • the subject has early stage Parkinson’s disease.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein, if excessive daytime sleepiness is measured in the subject, then a reduced excessive daytime sleepiness is observed in the subject relative to a control subject not receiving Parkinson’s disease therapy or relative to a control subject administered pramipexole monotherapy.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof and both rasagiline and pramipexole are slow released.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein, if excessive daytime sleepiness is measured in the subject by an Epworth Sleepiness Scale (ESS) score, then a reduced ESS score is observed in the subject relative to a control subject administered pramipexole monotherapy.
  • ESS Epworth Sleepiness Scale
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in excessive sleepiness in the subject compared to a control subject not receiving Parkinson’s disease therapy or relative to a control subject administered pramipexole or rasagiline monotherapy.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.
  • the fixed dose combination comprises pramipexole dihydrochloride monohydrate. In some embodiments, the fixed dose combination comprises rasagiline mesylate.
  • the fixed dose combination comprises from about 0.1 mg to about 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and from about 0.1 mg to about 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 gr of pramipexole dihydrochloride monohydrate based on the mass of pramipexole, and 0.75 mg of rasagiline mesylate based on the mass of rasagiline.
  • the fixed dose combination is in a form of a capsule, a tablet, a pill, a dragee, a powder, a granule, an emulsion, a solution, or a suspension.
  • the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the fixed dose combination provides an extended release of the rasagiline or pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the rasagiline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the administering is once-daily.
  • the excessive daytime sleepiness is measured by an Epworth Sleepiness Scale (ESS) score.
  • ESS Epworth Sleepiness Scale
  • the fixed dose combination effectuates a reduction in excessive daytime sleepiness in the subject relative to a control subject not receiving Parkinson’s disease therapy.
  • the fixed dose combination effectuates a reduction in excessive daytime sleepiness in the subject relative to a control subject administered pramipexole monotherapy.
  • the treating Parkinson’s disease or a symptom thereof is measured by a Unified Parkinson’s Disease Rating Scale (UPDRS), wherein the fixed dose combination is effective at reducing a total UPDRS score in the subject relative to baseline.
  • UPDRS Unified Parkinson’s Disease Rating Scale
  • the fixed dose combination provides superior efficacy at treating Parkinson’s disease or a symptom thereof while reducing excessive daytime sleepiness in the subject compared to a control subject receiving an individual component of the fixed dose combination.
  • the fixed dose combination provides substantially comparable efficacy at treating Parkinson’s disease or a symptom thereof while reducing excessive daytime sleepiness in the subject compared to a control subject receiving a treatment regimen comprising pramipexole or a pharmaceutically-acceptable salt thereof.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof is about 6 mg or from about 1.5 mg to about 4.5 mg.
  • the subject has early stage Parkinson’s disease.
  • a method of treating early stage Parkinson’s disease in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in excessive sleepiness in the subject compared to a control subject administered pramipexole monotherapy.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof and both rasagiline and pramipexole are slow released.
  • a method of reducing, avoiding, diminishing, treating or ameliorating excessive daytime sleepiness in a human subject having Parkinson’s disease, or who is receiving a treatment regimen for Parkinson’s disease comprising a dopamine agonist or a dopaminergic agent, comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof and both rasagiline and pramipexole are slow released.
  • the dopamine agonist or dopaminergic agent is one or more of levodopa, amantadine, selegiline, entacapone, ramelteon, melatonin, zolpidem, eszopiclone, zopiclone, brotizolam, trazodone, doxepin, darifenacin, solifenacin, tolterodine, pregabalin, gabapentin, enacarbil, paroxetine, donepezil, rivastigmine, desipramine, carbamazepine, clonazepam, lorazepam, triazolam, temazepam, flurazepam, cabergoline, rotigotine, suvorexant, pergolide, cabergoline, ropinirole, carbidopa, benserazide, clozapine, quetiapine, primavanesr
  • the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.
  • the fixed dose combination comprises pramipexole dihydrochloride monohydrate.
  • the fixed dose combination comprises rasagiline mesylate.
  • the fixed dose combination comprises from about 0.1 mg to about 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and from about 0.1 mg to about 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof. In some embodiments, the fixed dose combination comprises 0.6 gr of pramipexole dihydrochloride monohydrate based on the mass of pramipexole, and 0.75 mg of rasagiline mesylate based on the mass of rasagiline.
  • the fixed dose combination is in a form of a capsule, a tablet, a pill, a dragee, a powder, a granule, an emulsion, a solution, or a suspension.
  • the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the fixed dose combination provides an extended release of the rasagiline or a pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the rasagline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the administering is once-daily.
  • the excessive daytime sleepiness is measured by an Epworth Sleepiness Scale (ESS) score.
  • ESS Epworth Sleepiness Scale
  • the fixed dose combination effectuates a reduction in excessive daytime sleepiness in the subject relative to a control subject not receiving Parkinson’s disease therapy.
  • the fixed dose combination effectuates a reduction in excessive daytime sleepiness in the subject relative to a control subject administered pramipexole or rasagiline monotherapy.
  • the fixed dose combination is effective at treating Parkinson’s disease or a symptom thereof.
  • the fixed dose combination provides superior efficacy at treating Parkinson’s disease or a symptom thereof while reducing excessive daytime sleepiness in the subject compared to a control subject receiving an individual component of the fixed dose combination.
  • the fixed dose combination provides substantially comparable efficacy at treating Parkinson’s disease or a symptom thereof while reducing excessive daytime sleepiness in the subject compared to a control subject receiving a treatment regimen comprising pramipexole or a pharmaceutically-acceptable salt thereof.
  • the dose of pramipexole is 0.6 mg or more.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof is about 0.6 mg or from about 1.5 mg to about 4.5 mg.
  • the efficacy at treating Parkinson’s disease or a symptom thereof is measured by a Unified Parkinson’s Disease Rating Scale (UPDRS), wherein the fixed dose combination is effective at reducing a total UPDRS score in the subject relative to baseline.
  • UPDRS Unified Parkinson’s Disease Rating Scale
  • the subject has early stage Parkinson’s disease.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a pharmaceutical composition comprising a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein, if hallucinations or orthostatic hypoension are detected or measured in the subject, then reduced hallucinations or orthostatic hypotension are detected or measured in the subject relative to a control subject administered pramipexole monotherapy.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof.
  • a method of treating Parkinson’s disease or a symptom thereof in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in hallucinations or orthostatic hypotension in the subject compared to a control subject administered pramipexole monotherapy.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.
  • the fixed dose combination comprises pramipexole dihydrochloride monohydrate. In some embodiments, the fixed dose combination comprises rasagiline mesylate. In some embodiments, the fixed dose combination comprises from about 0.1 mg to about 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and from about 0.1 mg to about 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 gr of pramipexole dihydrochloride monohydrate based on the mass of pramipexole, and 0.75 mg of rasagiline mesylate based on the mass of rasagiline.
  • the fixed dose combination is in a form of a capsule, a tablet, a pill, a dragee, a powder, a granule, an emulsion, a solution, or a suspension.
  • the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the fixed dose combination provides an extended release of the rasagiline or pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the rasagiline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the administering is once-daily.
  • the fixed dose combination effectuates a reduction in hallucinations or orthostatic hypotension in the subject relative to a control subject not receiving Parkinson’s disease therapy.
  • the fixed dose combination effectuates a reduction in hallucinations or orthostatic hypotension in the subject relative to a control subject administered pramipexole or rasagiline monotherapy.
  • the treating Parkinson’s disease or a symptom thereof is measured by a Unified Parkinson’s Disease Rating Scale (UPDRS), wherein the fixed dose combination is effective at reducing a total UPDRS score in the subject relative to baseline.
  • UPDRS Unified Parkinson’s Disease Rating Scale
  • the fixed dose combination provides superior efficacy at treating Parkinson’s disease or a symptom thereof while reducing hallucinations or orthostatic hypertension in the subject compared to a control subject receiving an individual component of the fixed dose combination. In some embodiments, the fixed dose combination provides substantially comparable efficacy at treating Parkinson’s disease or a symptom thereof while reducing hallucinations or orthostatic hypertension in the subject compared to a control subject receiving a treatment regimen comprising pramipexole or a pharmaceutically-acceptable salt thereof.
  • the dose of pramipexole is 0.6 mg or more. In some embodiments, the dose of pramipexole or a pharmaceutically-acceptable salt thereof is about 0.6 mg or from about 1.5 mg to about 4.5 mg.
  • the subject has early stage Parkinson’s disease.
  • a method of treating early stage Parkinson’s disease in a subject in need thereof comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof, wherein the fixed dose combination effectuates a reduction in hallucinations or orthostatic hypertension in the subject compared to a control subject t administered pramipexole monotherapy.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof.
  • a method of reducing, avoiding, diminishing, treating or ameliorating hallucinations or orthostatic hypertension in a human subject having Parkinson’s disease, or who is receiving a treatment regimen for Parkinson’s disease comprising a dopamine agonist or a dopaminergic agent, comprising administering to the subject a fixed dose combination comprising from about 0.05 mg to about 1.0 mg pramipexole or a pharmaceutically-acceptable salt thereof, and from about 0.05 mg to about 1.0 mg rasagiline or a pharmaceutically-acceptable salt thereof.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof in the fixed dose formulation is lower than the dose of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the dopamine agonist or dopaminergic agent is one or more of levodopa, amantadine, selegiline, entacapone, ramelteon, melatonin, zolpidem, eszopiclone, zopiclone, brotizolam, trazodone, doxepin, darifenacin, solifenacin, tolterodine, pregabalin, gabapentin, enacarbil, paroxetine, donepezil, rivastigmine, desipramine, carbamazepine, clonazepam, lorazepam, triazolam, temazepam, flurazepam, cabergoline, rotigotine, suvorexant, pergolide, cabergoline, ropinirole, carbidopa, benserazide, clozapine, quetiapine, primavanesr
  • the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.
  • the fixed dose combination comprises pramipexole dihydrochloride monohydrate.
  • the fixed dose combination comprises rasagiline mesylate.
  • the fixed dose combination comprises from about 0.1 mg to about 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and from about 0.1 mg to about 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 mg of pramipexole or a pharmaceutically-acceptable salt thereof and 0.75 mg of rasagiline or a pharmaceutically-acceptable salt thereof.
  • the fixed dose combination comprises 0.6 gr of pramipexole dihydrochloride monohydrate based on the mass of pramipexole, and 0.75 mg of rasagiline mesylate based on the mass of rasagiline.
  • the fixed dose combination is in a form of a capsule, a tablet, a pill, a dragee, a powder, a granule, an emulsion, a solution, or a suspension.
  • the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the fixed dose combination provides an extended release of the rasagiline or a pharmaceutically-acceptable salt thereof.
  • the in-vivo half-life of the rasagline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.
  • the administering is once-daily.
  • the fixed dose combination effectuates a reduction in hallucinations or orthostatic hypertension in the subject relative to a control subject not receiving Parkinson’s disease therapy. In some embodiments, the fixed dose combination effectuates a reduction in hallucinations or orthostatic hypertension in the subject relative to a control subject administered pramipexole or rasagiline monotherapy.
  • the fixed dose combination is effective at treating Parkinson’s disease or a symptom thereof.
  • the fixed dose combination provides superior efficacy at treating Parkinson’s disease or a symptom thereof while reducing hallucinations or orthostatic hypertension in the subject compared to a control subject receiving an individual component of the fixed dose combination.
  • the fixed dose combination provides substantially comparable efficacy at treating Parkinson’s disease or a symptom thereof while reducing hallucinations or orthostatic blood pressurein the subject compared to a control subject receiving a treatment regimen comprising pramipexole or a pharmaceutically-acceptable salt thereof.
  • the dose of pramipexole or a pharmaceutically-acceptable salt thereof is about 6 mg or from about 1.5 mg to about 4.5 mg.
  • the efficacy at treating Parkinson’s disease or a symptom thereof is measured by a Unified Parkinson’s Disease Rating Scale (UPDRS), wherein the fixed dose combination is effective at reducing a total UPDRS score in the subject relative to baseline.
  • UPDRS Unified Parkinson’s Disease Rating Scale
  • the subject has early stage Parkinson’s disease.
  • the study was a 12- week, multinational, randomized, double-blind, double-dummy, active- controlled, parallel group study designed to determine the efficacy, safety, and tolerability of P2B001 compared to its individual components and to a calibration arm of pramipexole ER in people with early Parkinson’s disease. It was conducted at 70 centers in the US, Europe, and Canada.
  • P2B001 a once daily ER combination product (comprised of pramipexole 0.6 mg and rasagiline 0.75 mg); pramipexole ER capsule 0.6 mg once daily; rasagiline ER capsule 0.75 mg once daily; and the currently marketed product pramipexole ER capsules titrated to an optimal dose for each individual patient (1.5 to 4.5 mg).
  • the primary endpoint was the change in total Unified Parkinson's Disease Rating Scale (UPDRS, defined as the sum of parts II and III) for P2B001 as compared to each of its individual components over 12 weeks.
  • UPDS Unified Parkinson's Disease Rating Scale
  • P2B001 is a novel fixed-dose combination of extended release (ER) formulations of pramipexole (0.6mg) and rasagiline (0.75mg), with both components at lower doses than the respective marketed product.
  • ER extended release
  • P2B was superior to each of its individual components as measured by the change from baseline to week 12 in total Unified Parkinson's Disease Rating Scale (UPDRS Part II + III; primary endpoint).
  • P2B001 demonstrated comparable efficacy to a marketed pramipexole ER with significantly less daytime sleepiness (somnolence), by a reduction of 2.66 points (p ⁇ 0.0001) as measured by Epworth Sleepiness Scale (ESS; key secondary endpoint).
  • P2B001 fixed dose and a marketed pramipexole ER (titrated to an optimal dose for each individual patient; 1.5-4.5 mg) showed similar changes in total UPDRS scores after 12 weeks (-7.98 points and -8.35 points, respectively).
  • P2B001 can provide clinical benefits comparable to higher doses of commercially available dopamine agonists, while mitigating the side effects typically associated with this class of medicine such as somnolence, orthostatic hypotension and hallucinations. This is important for PD patients of all ages and is critical for the elderly, who typically do not tolerate side effects of dopamine agonists.
  • TEAE Treatment-emergent adverse events
  • P2B001 has the potential to become a leading treatment option for PD, particularly as first line therapy for early-stage patients of all ages.
  • P2B001 would enable patients to be treated with an effective dose of a dopamine agonist, yet with less adverse events often seen with this class of drugs, including daytime sleepiness, orthostatic hypotension, and hallucinations. These issues can often negatively affect patients’ activities of daily living.
  • P2B001 has the additional advantage of once-a-day administration without the need for titration.
  • P2B001 has the potential to offer a solution that is easy to use, provides good symptomatic control and a favorable safety profile, and may reduce or delay levodopa-associated motor complications. This product will be an important new option when considering a long-term care plan for people with early-stage Parkinson’s disease.
  • P2B001 contains both pramipexole and rasagiline formulated using a proprietary ER coating system. While ER pramipexole formulations have been available for over a decade, P2B001 contains the first ER formulation of rasagiline.
  • Pramipexole has an absolute oral bioavailability greater than 90%, with steady absorption across the intestine including the colon, and little first pass metabolism. It exhibits linear pharmacokinetics and less than 20% is protein bound; more than 90% of the absorbed dose is eliminated unchanged and almost exclusively by the kidneys. Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 1 hour.
  • the absolute bioavailability of rasagiline is about 36% and plasma protein binding ranges from 88-94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1 100 ng/mL.
  • the mean UC and Cmax for rasagiline and 1 -aminoindan are linearly proportional to the rasagiline dose.
  • Rasagiline undergoes almost complete biotransformation in the liver prior to excretion.
  • the metabolism of rasagiline proceeds through two main CYP-450 dependent pathways: N-dealkylation and/or hydroxylation to yield 1-aminoindan (major active metabolite), 3-hydroxy-N-propargyl-l aminoindan and 3-hydroxy- 1 -aminoindan.
  • Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion is the major elimination pathway.
  • MAO-B inhibition of rasagiline Because of its irreversible inhibition of MAO-B, although (as reviewed above) other unknown mechanisms of efficacy may be in effect.
  • a comparative bioavailability study was performed in healthy volunteers to assess the relative rasagiline and pramipexole systemic exposure of P2B001.
  • the study compared a single dose of P2B001 (0.6 mg ER-pramipexole /0.75 mg ER-rasagiline) with the combination of branded pramipexole-ER (Mirapex ER®, Boehringer Ingelheim, Germany) plus branded rasagiline (Azilect®, Teva Pharmaceuticals, Israel) at currently used doses (0.75mg and 1 mg, respectively).
  • the overall pharmacokinetic profile of the P2B001 pramipexole component was similar to that seen with the branded pramipexole ER plus rasagiline combination (albeit with lower Cmax and AUC due to lower dosing), while the Cmax of the P2B001 rasagiline component was significantly lower (from 5774 to 537 pg/mL) and the ti/2 significantly longer (from 3.9 to 12.5 hours) than that obtained with the branded rasagiline ( Figure 1A and Table 2).
  • both drug components in P2B001 are slowly released simultaneously throughout the day.
  • This profile reflects the desired change to an ER rasagiline formulation in which Cmax is significantly lower, a sharp peak is avoided, and the half- life is extended while maintaining a comparable AUC.
  • the findings support the safety profile of P2B001 as the overall exposure is lower than the component products with established safety profiles.
  • the Cmax and AUC of both rasagiline and pramipexole are approximately 2-fold higher than after the first dose of P2B001.
  • Significant differences versus placebo were seen as early as Week 4 for the 0.6/0.75mg dose group and by Week 8 for the 0.3/0.75mg dose group ( Figure 2).
  • the placebo-adjusted magnitude of change for the 0.6/0.75mg dose group is considered clinically relevant and was higher (5.7 points in the P2B001 0.6/0.75mg group and 4.6 points in the P2B001 0.3/0.75mg group) when an outlier site that recorded marked placebo effects was excluded in post- hoc analysis.
  • the symptomatic benefits observed with P2B001 compare well with the efficacy reported in randomized, placebo-controlled trials of the marketed higher dose of the separate components. For example, treatment with pramipexole (1.5 mg/day) improved Total UPDRS scores by 5.2 points relative to placebo at Week 10 in the STEP-UP clinical trial and by 4.8 points at 9 months in the PROUD study.
  • each patient takes one capsule and 1-3 tablets once daily.
  • the capsules contained either P2B001 (0.6/0.75mg) or pramipexole (0.6 mg) or rasagiline (0.75 mg) or matching placebo.
  • the tablets contained either pramipexole ER (0.375 mg) or pramipexole ER (1.5 mg) or matching placebo (Figure 3).
  • the titration of the pramipexole ER/matching placebo will be increased by weekly increments up to a daily dose of 1.5 mg as follows: 0.375, 0.75 and 1.5 mg.
  • the titration can continue to a daily dose of 3.0 mg or 4.5 mg of pramipexole ER or matching placebo or reduced to a minimum of 1.5mg with the final level determined based on achieving satisfactory efficacy and tolerability.
  • the minimum therapeutic dose of pramipexole ER 1.5 mg per day (or placebo) must be achieved.
  • the treatment with study medications of patients who cannot achieve this dosage will be discontinued, but the subject will be requested to continue with all the study visits. After 12 weeks, all patients were gradually down titrated over 7 days, with either active pramipexole ER or placebo.
  • the primary objective was to determine the superiority of P2B001 0.6/0.75 mg as compared to its individual components in the change of total UPDRS (parts II+III) score.
  • Main Secondary objective was superiority of P2B001 vs. marketed pramipexole ER (titrated doses) in ESS in addition to additional assessments effects on UPDRS motor and ADL subscales.
  • Safety assessments included QUIP- RS (questionnaire for Impulsive Compulsive Rating Scale, CSS-RS (Columbia-Suicide Severity Rating Scale) orthostatic hypotension and the proportion of patients with somnolence , other dopaminergic effects including gastrointestinal adverse events, hallucinations and the like.
  • Somnolence which can lead to falls, injury and difficulties driving, is a common occurrence in patients receiving pramipexole at doses of 1.5 mg/day (0.5 mg three times a day) and above for PD. While somnolence was experienced more frequently with P2B001 than placebo in the Phase II study, its incidence was lower than experienced across the pramipexole pivotal studies in early PD (16% with P2B001 and 22% with pramipexole ). Indeed, placebo-adjusted changes from baseline in ESS score with P2B001 were comparable to placebo and less than has been reported with higher doses of pramipexole in early PD (0.5 vs. 1.0-2.1) in early PD.
  • Table 3 compares the safety and tolerability of P2B001 (0.6/0.75mg) in the phase II trial with the safety of pramipexole in previous placebo-controlled studies of similar duration.
  • combination therapies offer the potential of mechanistic synergy with efficacy going beyond that provided by individual components.
  • combining mechanisms of action offers the opportunity for dose saving, which in itself can improve safety and tolerability.
  • the aim is to leverage the complementary mechanisms of rasagiline and pramipexole in early PD, where the patient’s remaining central dopamine reserves are enhanced by MAO-B inhibition with rasagiline while pramipexole provides prolonged dopamine receptor stimulation.
  • dopamine agonist monotherapy as initial therapy as a way to delay the initiation of levodopa or to decrease the total exposure to levodopa, thereby reducing the motor complications of long-term levodopa therapy.
  • Dopamine agonists when used alone, rarely promote the development of dyskinesias and motor fluctuations that complicate levodopa treatment.
  • Temporal profile graphs of adverse events (AEs) of Phase III study enabled the visualization of the frequency and duration of each event during the course of the trial. For each time point (0-100 treatment days) the percent of subjects with specific AEs is presented (Olanow et al 2018, Adverse Event Reporting in Clinical Trials in Parkinson’s Disease: Time for Change, Movement Disorders, 2018 1-3, DOI: 10.1002/mds.27497).
  • the temporal profile of dopaminergic AEs i.e orthostatic hypotension, impulsive Compulsive Disorder (ICD), constipation, dizziness, hallucination, nausea, oedema, somnolence, sleep disorder as depicted in Figure 4 illustrates that these AEs were markedly more frequent and longer lasting in the PramiER group than in the P2B001 group
  • Temporal profile graphs of gastrointestinal (GI) adverse events (AEs) of Phase III study enabled the visualization of the frequency and duration of each event during the course of the trial. For each time point (0-100 treatment days) the percent of subjects with specific GI AEs is presented (Olanow et al 2018, Adverse Event Reporting in Clinical Trials in Parkinson’s Disease: Time for Change, Movement Disorders, 2018 1-3, DOI: 10.1002/mds.27497).
  • GI AEs i.e constipation, nausea, vomiting, diarrhoea, abdominal pain upper, abdominal discomfort, gastritis, dyspepsia, gastroesophageal reflux disease, flatulence, as depicted in Figure 5 illustrates that these GI-TEAEs were markedly more frequent and longer lasting in the PramiER group than in the P2B001 group.

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Abstract

L'invention concerne une méthode de traitement de la maladie de Parkinson ou d'un symptôme de celle-ci chez un sujet en ayant besoin, comprenant l'administration au sujet d'une composition pharmaceutique comprenant une combinaison à dose fixe de pramipexole et de rasagiline ou d'un sel pharmaceutiquement acceptable de ceux-ci, dans laquelle, si une somnolence diurne excessive est mesurée chez le sujet, alors une réduction de la somnolence diurne excessive est observée chez le sujet par rapport à un sujet témoin auquel on a administré du pramipexole en monothérapie. L'invention concerne en outre une méthode de traitement de la maladie de Parkinson ou d'un symptôme de celle-ci chez un sujet en ayant besoin, comprenant l'administration au sujet d'une combinaison à dose fixe, la combinaison à dose fixe entraînant une réduction des effets indésirables apparus au cours du traitement (TEAE), y compris un ou plusieurs parmi l'hypotension orthostatique, ICD, la constipation, les vertiges, les hallucinations, les nausées, les œdèmes, la somnolence, les troubles du sommeil, par rapport à un sujet témoin auquel on a administré du pramipexole en monothérapie.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
IL233572A0 (en) * 2012-01-12 2014-08-31 Nurit Livnah A pharmaceutical preparation containing a mixture with fixed doses for the treatment of Parkinson's disease

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Publication number Priority date Publication date Assignee Title
IL233572A0 (en) * 2012-01-12 2014-08-31 Nurit Livnah A pharmaceutical preparation containing a mixture with fixed doses for the treatment of Parkinson's disease

Non-Patent Citations (2)

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Title
ANONYMOUS: "A Phase 3 Study With P2B001 in Subjects With Early Parkinson's ", CLINICALTRIALS.GOV ID NCT03329508, 20 May 2021 (2021-05-20), XP093071372, Retrieved from the Internet <URL:https://clinicaltrials.gov/study/NCT03329508?tab=history&a=29> [retrieved on 20230807] *
OLANOW C. WARREN, KIEBURTZ KARL, LEINONEN MIKA, ELMER LAWRENCE, GILADI NIR, HAUSER ROBERT A., KLEPISKAYA OLGA S., KREITZMAN DAVID : "A randomized trial of a low-dose Rasagiline and Pramipexole combination (P2B001) in early Parkinson's disease : Randomized Trial of P2B001 in Early PD", MOVEMENT DISORDERS, RAVEN PRESS, NEW YORK, NY, US, vol. 32, no. 5, 1 May 2017 (2017-05-01), US , pages 783 - 789, XP055776702, ISSN: 0885-3185, DOI: 10.1002/mds.26941 *

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