BACKGROUND OF THE INVENTION

Parkinson’s disease (PD) 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.

SUMMARY OF THE INVENTION

According to some embodiments, there is provided 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.

According to some embodiments, there is provided 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.

According to some embodiments, there is provided 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.

According to some embodiments, there is provided 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.

According to some embodiments, there is provided 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, the treatment regimen 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. According to some embodiments, there is provided 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.

According to some embodiments, there is provided 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.

According to some embodiments, there is provided 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.

According to some embodiments, there is provided 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.

According to some embodiments, there is provided a method of reducing, avoiding, diminishing, treating or ameliorating treatment-emergent adverse events (TEAEs), 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. According to some embodiments, there is provided a method of reducing, avoiding, diminishing, treating or ameliorating treatment-emergent adverse events (TEAEs), 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.

In some embodiments, 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. In some embodiments, 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.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how the several forms of the invention may be embodied in practice.

In the drawings:

Figure 1 (A, B, C and D) 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.

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.

DETAILED EMBODIMENTS OF THE INVENTION

The principles, uses, and implementations of the teachings herein may be better understood with reference to the accompanying description and figures. Upon perusal of the description and figures present herein, one skilled in the art will be able to implement the teachings herein without undue effort or experimentation. In the figures, same reference numerals refer to same parts throughout.

Once diagnosed, it is now generally agreed that there is no clinical rationale to postpone symptomatic treatment in people who develop PD-related disability. Conventional pharmacotherapy for motor symptom control is primarily based on dopaminergic replacement strategies. Current European guidelines recommend levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors as having Level A evidence for the treatment of early untreated PD. 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). By contrast, 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. A notable exception are younger patients, aged less than 60 years, who are at higher risk for the development of dyskinesia. Such patients are not only more prone to dyskinesias but also more likely to have the longest levodopa treatment duration and live the longest with motor complications once they develop. Highly effective long-term treatment strategies that avoid motor complications remains an unmet need. There is compelling evidence that most patients treated with levodopa will develop motor complications within 2-5 years and many will experience decreased quality of life and function. Dopamine agonists are efficacious in early disease and delay the onset of motor complication but are associated with significant, often dose-dependent, safety risks such as impulse control disorders, somnolence and hallucinations that can limit their utility. As such they have been typically suggested for patients younger than 60, who are more prone to develop dyskinesias (as in the new AAN guidelines, and at early disease stages, when milder parkinsonism does not demand using the strongest drug available. 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.

Excessive daytime sleepiness (EDS) is a common symptom in Parkinson's Disease (PD) patients, with prevalence ranging from 15 to 50%. Importantly, 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. Furthermore, 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.

Surprisingly, it was found that administration of P2B001, once a day, to early-stage Parkinson's disease patients showed less daytime sleepiness in comparison to marketed pramipexole ER (titrated to optimal dose) treatment, wherein the efficacy of the treatment was maintained. Interestingly, there was also a significant benefit of P2B001 (the combination of rasagiline ER 0.75 mg and pramipexole ER 0.6mg) vs. the component pramipexole ER 0.6mg (PPX0.6) while there was no statistically significant difference between P2B001 and its rasagiline component.

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. In one embodiment, term "excessive daytime sleepiness" (EDS), as used herein, is to be understood as ESS score of more than 10.

General Terms

The term "Parkinson's disease" (PD), as used herein, is to be understood, for example, according to the Hoehn and Yahr scale [e.g. in Neurology, 1967, 17 (5): 427-442; or in Mov Disord. 2004 September; 19(9): 1020-8 and modified to by Larsen (Larsen TA, LeWitt PA, Caine DB. Theoretical and practical issues in assessment of deficits and therapy in parkinsonism. Lisunde and other dopamine agonists. 1983:363-73.], which is incorporated herein by reference. In one embodiment "PD", as used herein, refers to "early-stage PD", "mid-stage PD" and "advanced-stage PD". As used herein, the term "early-stage PD", refers to stages <3 (0, 0.0- 2.5) the term "mid-stage PD" refers to stage 3, and the term "advanced-stage PD", refers to stage 4 and 5; wherein stages are according to the Hoehn and Yahr scale [Neurology, 1967, 17 (5): 427-442], In one embodiment, PD refers to "early-stage PD". In another embodiment, PD refers to "mid-stage PD". In yet another embodiment, PD refers to "advanced-stage PD".

As used herein, the term "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).

The term "dopamine-replacement therapy", as used herein, 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).

The term "excessive daytime sleepiness associated with dopamine therapy in Parkinson's disease", also termed here "somnolence" as used herein, is to be understood, for example, according to ICSD- 3 criteria (i.e. according to the International Classification of Sleep Disorders-third Ed.: American Academy of Sleep Medicine, 2014) as defined for hypersomnia due to a medication or substance, such as hypersomnia due to dopamine replacement therapy. 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. all A-C below) for the diagnosis: (A) the patient has daily periods of irrepressible need to sleep or daytime lapses into sleep, (B) the daytime sleepiness occurs as a consequence of current medication or substance use or withdrawal from a wake-promoting medication or substance, (C) the symptoms are not better explaineds by another untreated sleep disorder, medical or neurological disorder, or mental disorder. In some embodiments, the method of treating of the invention promotes wakefulness. In some embodiments, 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. decrease in 2 points) or as measured by the Maintenance of Wakefulness Test (e.g. at least 0.5 minute increase of sleep latency). In one embodiment, 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". In another embodiment, the term "for a treatment promoting wakefulness", as used herein, is to be understood as "for a method of treatment promoting wakefulness". As used herein, 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). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those, which may not be discernible by the patient. In yet another embodiment, "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 term "alleviating" or "alleviation", for example in reference to a symptom of a condition, as used herein, refers to reducing at least one of the frequency and amplitude of a symptom of a condition in a patient. In one embodiment, the terms "method for the treatment" or "method for treating", as used herein, refer to "method to treat".

In some embodiments, 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 the subject over a defined period of time, as measured by one or more medically recognized technique; and/or (f) the method results in a decreased severity of hallucinations 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; and/or (h) the medically recognized technique selected from the group consisting of Chicago Hallucination Assessment Tool (CHAT), The Psychotic Symptom Rating Scales (PSYRATS), Auditory Hallucinations Rating Scale (AHRS), Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ), Characteristics of Auditory Hallucinations Questionnaire (CAHQ), Mental Health Research Institute Unusual Perception Schedule (MUPS), positive and negative syndrome scale (PANSS), scale for the assessment of positive symptoms (SAPS), Launay-Slade hallucinations scale (LSHS), the Cardiff anomalous perceptions scale (CAPS), and structured interview for assessing perceptual anomalies (SIAPA); and/or (i) each defined period of time is independently selected from the group consisting of about 1 day to about 10 days, about 10 days to about 30 days, about 30 days to about 3 months, about 3 months to about 6 months, about 6 months to about 12 months, and about greater than 12 months. "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.

"Controlling or reducing orthostatic hypotension" in some embodiments, the methods of the present disclosure minimize orthostatic hypotension. In some embodiments, the method is substantially devoid of orthostatic hypotension. In some embodiments, the risk of orthostatic hypotension in the patient is about the same as or similar to placebo. In some embodiments, the method results in orthostatic hypotension in less than or equal to 2.7% of patients. In some embodiments, 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. In some embodiments, the method results in orthostatic hypotension in a percentage of patients that is no more than placebo. In some embodiments, 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. The term "patient", as used herein, refers to a subject who is diseased and would benefit from the treatment. The term "elderly patient", as used herein, refers to a patient sixty-five years of age or older.

As used herein, the term "subject" refers to a mammalian organism, preferably a human being (male or female).

As used herein, a subject is "in need of' a treatment if such subject (patient) would benefit biologically, medically or in quality of life from such treatment.

The term "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. The term "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.

The term "pharmaceutical 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.

As used herein, “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. For example, 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. In some embodiments, the salt is mesylate, which is any salt or ester of methanesulfonic acid (CH3SO3H). Lists of suitable salts are found in texts such as Remington's Pharmaceutical Sciences, 18 ^th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, Pa., 1990); Remington: the Science and Practice of Pharmacy 19.sup.th Ed. (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3.sup.rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999); the Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12 ^th Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference.

In some embodiments, the rasagiline is rasagiline mesylate.

In some embodiments, the pramipexole is pramipexole dihydrochloride monohydrate.

In some embodiments, 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.

In some embodiments, wherein 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.

In some embodiments, 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.

As used herein, 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). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. The term “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, cabergoline, rotigotine, suvorexant, pergolide, pramipexole, cabergoline, ropinirole, carbidopa, benserazide, clozapine, quetiapine, primavanesrin, duloxetine, mirtazapine, nortriptyline, venlafaxine, modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine and sodium oxybate; or pharmaceutically acceptable salts thereof; as well as modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, alprazolam, solriamfetol, and sodium oxybate; or pharmaceutically acceptable salts thereof.

As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

P2B001 and its components

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.

Chemistry and pharmacodynamics of P2B001 components

Pramipexole

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. Whereas in the intact striatum, stimulation of presynaptic autoreceptors of the D3 and D2 type is thought to reduce the synthesis and synaptic release of dopamine, in the parkinsonian state, the postsynaptic D3 and D2 receptors on the striatofugal neurons of the direct and indirect pathways are additionally stimulated. Here, it is hypothesized that pramipexole corrects the increased inhibitory impact of the direct pathway on motor activity by enhancing the direct transmission (through D3 receptors) and reducing the indirect transmission (through D2 receptors) thereby mimicking dopamine’s effects in the striatum. Several potential mechanisms for neuroprotection have also been proposed including antioxidant/free radical scavenging actions, trophic mechanisms (e.g via Bcl-2), protection against apoptosis and D3 receptor mediated activation of branching and neurite extension. However, interpretation of the preclinical data has been hampered by differences among models and by uncertainties concerning each model's mimicry of PD.

The symptomatic efficacy of pramipexole in early PD is well established. While its effect size is inferior to levodopa, 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. However, there are safety concerns, including the induction of daytime sleepiness and sudden-onset sleep as well as impulse control disorders including pathological gambling, hypersexuality, binge eating and pathological shopping. These side effects are often dose related, with higher doses resulting in a higher risk compared with small to medium doses.

Rasagiline

Rasagiline (N-propargyl-l-(R)-aminoindan) is a potent and irreversible inhibitor of monoamine oxidase type B (MAO-B), which is attributed to irreversible covalent binding of its propargyl moiety to the flavin adenine dinucleotide (FAD) moiety of the enzyme. By binding to FAD moiety, 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. Such effects are thought to be driven at the mitochondrial level where propargylamine exerts its effects on apoptosis via mechanisms such as the downregulation of Bax and Bad proteins, the induction of Bel- 2 and Bcl-xL proteins, the induction of GDNF and BDNF, and stimulation of protein kinase C phosphorylation.

The symptomatic efficacy and safety of rasagiline monotherapy in early disease has also been firmly established by RCT’s. Most patients on monotherapy with a MAO-B inhibitor will require additional therapy within 2 to 3 years"Rasagiline monotherapy is generally very well tolerated with little difference in the rate of adverse events between rasagiline and placebo.

In some embodiments, there is provided 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.

In some embodiments, 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.

In some embodiments, there is provided 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.

In some embodiments, 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. In some embodiments, the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.

In some embodiments, 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.

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.

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.

In some embodiments, 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.

In some embodiments, the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the fixed dose combination provides an extended release of the rasagiline or pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the rasagiline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the administering is once-daily.

In some embodiments, 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.

In some embodiments, 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. In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the subject has early stage Parkinson’s disease.

In some embodiments, there is provided 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.

In some embodiments, 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.

In some embodiments, there is provided a method of reducing, avoiding, diminishing, treating or ameliorating treatment-emergent adverse events (TEAEs), 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. In some embodiments, 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. In some embodiments, 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, primavanesrin, duloxetine, mirtazapine, nortriptyline, venlafaxine, modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sodium oxybate; modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, alprazolam, solriamfetol, and sodium oxybate; or pharmaceutically-acceptable salts thereof.

In some embodiments, the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.

In some embodiments, 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.

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.

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.

In some embodiments, 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.

In some embodiments, the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the fixed dose combination provides an extended release of the rasagiline or a pharmaceutically-acceptable salt thereof. In some embodiments, the in-vivo half-life of the rasagline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the administering is once-daily.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the fixed dose combination is effective at treating Parkinson’s disease or a symptom thereof.

In some embodiments, 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 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.

In some embodiments, 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. In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the subject has early stage Parkinson’s disease.

In some embodiments, there is provided 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.

In some embodiments, 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.

In some embodiments, there is provided 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.

In some embodiments, 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.

In some embodiments, there is provided 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.

In some embodiments, 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.

In some embodiments, the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.

In some embodiments, 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.

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.

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.

In some embodiments, 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.

In some embodiments, the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof. In some embodiments, the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the fixed dose combination provides an extended release of the rasagiline or pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the rasagiline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the administering is once-daily.

In some embodiments, the excessive daytime sleepiness is measured by an Epworth Sleepiness Scale (ESS) score.

In some embodiments, 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.

In some embodiments, the fixed dose combination effectuates a reduction in excessive daytime sleepiness in the subject relative to a control subject administered pramipexole monotherapy.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the subject has early stage Parkinson’s disease.

In some embodiments, there is provided 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. In some embodiments, 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.

In some embodiments, there is provided 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, 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. In some embodiments, 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.

In some embodiments, 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, primavanesrin, duloxetine, mirtazapine, nortriptyline, venlafaxine, modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sodium oxybate; modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, alprazolam, solriamfetol, and sodium oxybate; or pharmaceutically-acceptable salts thereof.

In some embodiments, the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.

In some embodiments, 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.

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. 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.

In some embodiments, 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.

In some embodiments, the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the fixed dose combination provides an extended release of the rasagiline or a pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the rasagline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the administering is once-daily.

In some embodiments, the excessive daytime sleepiness is measured by an Epworth Sleepiness Scale (ESS) score.

In some embodiments, 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.

In some embodiments, the fixed dose combination effectuates a reduction in excessive daytime sleepiness in the subject relative to a control subject administered pramipexole or rasagiline monotherapy.

In some embodiments, the fixed dose combination is effective at treating Parkinson’s disease or a symptom thereof.

In some embodiments, 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.

In some embodiments, 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. In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the subject has early stage Parkinson’s disease.

In some embodiments, there is provided 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.

In some embodiments, 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.

In some embodiments, there is provided 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.

In some embodiments, 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.

In some embodiments, the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.

In some embodiments, 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.

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.

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.

In some embodiments, 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.

In some embodiments, the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the fixed dose combination provides an extended release of the rasagiline or pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the rasagiline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the administering is once-daily.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the subject has early stage Parkinson’s disease.

In some embodiments, there is provided 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.

In some embodiments, 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.

In some embodiments, there is provided 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, 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. In some embodiments, 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.

In some embodiments, 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, primavanesrin, duloxetine, mirtazapine, nortriptyline, venlafaxine, modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, sodium oxybate; modafinil, armodafinil, caffeine, methylphenidate, dextroamphetamine, alprazolam, solriamfetol, and sodium oxybate; or pharmaceutically-acceptable salts thereof.

In some embodiments, the fixed dose combination further comprises a pharmaceutically-acceptable carrier or excipient.

In some embodiments, 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.

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.

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.

In some embodiments, 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.

In some embodiments, the fixed dose combination provides an extended release of the pramipexole or pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the pramipexole or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the fixed dose combination provides an extended release of the rasagiline or a pharmaceutically-acceptable salt thereof.

In some embodiments, the in-vivo half-life of the rasagline or pharmaceutically-acceptable salt thereof is at least about 12 hours after administration.

In some embodiments, the administering is once-daily.

In some embodiments, 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.

In some embodiments, the fixed dose combination is effective at treating Parkinson’s disease or a symptom thereof.

In some embodiments, 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 blood pressurein the subject compared to a control subject receiving a treatment regimen comprising pramipexole or a pharmaceutically-acceptable salt thereof.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the subject has early stage Parkinson’s disease.

EXAMPLES

Example 1

Phase 3 Study Design

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. A total of 544 participants were randomized to one of four treatment arms: 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. Secondary endpoints included a comparison of P2B001 with the calibration arm (currently marketed pramipexole ER) with regard to changes in the Epworth Sleepiness Scale (ESS) score, as well as comparison of P2B001 to its individual components in the motor (Part III) and activities of daily living (Part II) components of the UPDRS score.

Phase III double-blind, active-controlled study of P2B001 in early Parkinson’s disease (PD) successfully met its primary and key secondary endpoints.

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. In the phase III, 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 was superior to the pramipexole component by 2.66 points (p=0.0018) and superior to the rasagiline component by 3.30 points (p=0.0001).

In addition, 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).

The data from this Phase III study support the view that 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.

Brief summary of the results

P2B001 Met Primary Endpoint

• The adjusted mean change from baseline to week 12 in Total -UPDRS score was -2.66 points for P2B001 versus pramipexole 0.6 mg (p=0.0018) and -3.30 points for P2B001 versus rasagiline 0.75 mg (p=0.0001)

P2B001 Met Key Secondary Endpoint

• The adjusted mean change from baseline to week 12 in ESS score for P2B001 versus the marketed pramipexole ER was -2.66 points (p<0.0001) Calibration of P2B001 and Pramipexole ER

• The adjusted mean change in total UPDRS score from baseline to week 12 for P2B001 (-7.98 points) and the marketed pramipexole ER (-8.35 points) are comparable. A post-hoc noninferiority analysis showed that P2B001 was not inferior to pramipexole ER using a margin of 3 points.

P2B001 Showed a Favorable Side Effect Profile

• P2B001 was generally well tolerated, with more than 98% of treatment- emergent adverse events (TEAEs) being mild or moderate in severity. Early treatment termination rates were similar across treatment groups (between 7.1% - 9.1%).

• Treatment-emergent adverse events (TEAE) reported in >5% of participants in any arm are shown in table 1.

Table 1 Treatment Emerged Adverse Events Reported in 5% or More Frequency in Any Arm Based on the data from this well-designed, rigorous, placebo-controlled study, P2B001 has the potential to become a leading treatment option for PD, particularly as first line therapy for early-stage patients of all ages. The results demonstrated both superior efficacy to components and a more favorable safety profile than treatment with standard doses of pramipexole. 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.

Since the prevalence of Parkinson’s disease increases with age, and it is the fastest growing neurological disorder across the globe. With increased life expectancy and longer disease duration, patients will often require dopaminergic replacement therapies for many years. 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.

Example 2

Pharmacokinetics and metabolism of P2B001

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. At steady-state, 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. There is no correlation of pharmacokinetics with the 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). Thus, 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. Moreover, the findings support the safety profile of P2B001 as the overall exposure is lower than the component products with established safety profiles. At steady state, the Cmax and AUC of both rasagiline and pramipexole are approximately 2-fold higher than after the first dose of P2B001.

Table 2

Comparative pharmacokinetics ofP2B001 components versus branded products

33

SUBSTITUTE SHEET (RULE 26)

All data are mean ± SD

In a separate multidose study conducted in healthy volunteers, both pramipexole and rasagiline reached steady state after 5 days of administration (Figure IB).

P2B001 Clinical efficacy

Phase II clinical study of two doses of P2B001 versus placebo

The efficacy and safety of the current P2B001 formulation (0.6 mg pramipexole-ER/0.75 mg rasagiline) and a lower pramipexole dose formulation (0.3 mg pramipexole-ER/0.75 mg rasagiline) were tested in a Phase II clinical 12- week multicenter double-blind, placebo-controlled clinical trial. In this study, untreated patients with early PD (the mean duration of PD was 6.3 months) were randomized to once-daily treatment with P2B001 (0.3mg pramipexole/0.75mg rasagiline), P2B001 (0.6mg pramipexole/0.75mg rasagiline) or placebo.

The placebo-adjusted mean change from baseline to Week 12 in Total-UPDRS (parts 1+11+111) score (primary end point) was -4.7 points for the P2B001 0.6/0.75mg group (P=0.0004) and -3.8 points for the P2B001 0.3/0.75 mg group (P=0.003). 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. Moreover, 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. Similarly, in the pramipexole PRAMI-BID study, patients treated with pramipexole (1-1.5 mg/day) showed placebo-adjusted improvements of 4.4 - 4.7 Total UPDRS points at Week 12. Treatment with rasagiline (1 mg/day) improved Total UPDRS scores by 4.2 points relative to the placebo group (which showed significant worsening over time) at Week 26 of the TEMPO study and by 3.0 points at -Week 36 in the ADAGIO study.

The significant effects of the 0.6/0.75mg dose of P2B001 on quality of life also compares favorably with the results seen with pramipexole monotherapy in the PRAMI-BID study. Whereas treatment with P2B001 (0.6/0.75mg) significantly improved PDQ-39 Total, ADL and Mobility scores versus placebo, these benefits were only achieved in the PRAMI-BID study when pramipexole was given at the higher total daily dose of 1.5 mg/day (given 0.75mg BID or 0.5mg TID). Effects on PDQ-39 scores were not significantly different from placebo for the pramipexole 1.0 mg/day (0.5mg BID) dose group.

Example 3

Phase III clinical study comparing P2B001 with its individual components

To answer the question of how P2B001 0.6/0.75 mg dose compares to its individual components, 544 eligible subjects with early untreated PD were randomized (2:2:2: 1) to double-blind treatment with once daily P2B001, pramipexole (0.6 mg once daily) alone, rasagiline (0.75 mg once daily) alone, or pramipexole ER titrated to optimal dose (active calibration arm; 1.5, 3.0 or 4.5mg).

To maintain blinding, patients were treated using a double-dummy design where 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). For the first 3 weeks 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. If needed, between weeks 3 and 6, 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. On completion of the dose-titration phase (end of Week 6), 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.

Safety and tolerability of P2B001

In terms of safety and tolerability, as reported in the phase 2 study, P2B001 was well tolerated with an adverse event profile similar to placebo, with the exception of mild and transient nausea and somnolence, known adverse events of pramipexole, although somnolence was not significantly different than placebo when evaluated using the ESS.

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. While the proportion of patients who shifted to having an ESS score >10 was similar for P2B001 (0.6/0.75mg) to placebo (both 6%), it was less than the 16% reported with pramipexole IR and 21% with pramipexole ER (versus 8% with placebo) across earlier studies with pramipexole.

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. There were no reports of impulse control disorder, hallucinations or psychosis with P2B001 in the 12-week Phase II study. While hallucinations were already seen in >5% of patients treated with pramipexole 1.5mg within 10 weeks of the STEP-UP study and in 16.5% of patients receiving pramipexole (up to 4.5 mg/day) across the early PD pivotal trials, these psychiatric adverse events often develop over a longer time-frame with higher doses of pramipexole, and a longer duration of observation is required before drawing firm conclusions

These data suggest that a low dose, extended release, combination of pramipexole and rasagiline may be a safe and effective way to initiate therapy for patients with early PD. Patients who do not yet require levodopa therapy may prefer to take a once daily medication that offers good symptom control with an adverse event profile similar to placebo. Table 3 Adverse events reported with P2B001 in the Phase II study compared with data from previous randomized, placebo-controlled trials of pramipexole

The potential role for P2B001 in early Parkinson’s disease

The therapeutic potential of polytherapy using fixed combinations of agents with established symptomatic efficacy has remained virtually unexplored in the field of PD. In principle, combination therapies offer the potential of mechanistic synergy with efficacy going beyond that provided by individual components. As seen in other fields of medicine , combining mechanisms of action offers the opportunity for dose saving, which in itself can improve safety and tolerability. In the case of P2B001 , 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. When given at doses that would be considered subtherapeutic as separate agents, together they have been shown to provide clinically relevant efficacy with a low propensity for adverse events.

In the 1990s there was a significant push to use 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. However, the realization that dopamine agonist monotherapy was associated with dose-related adverse events such as somnolence, hallucinations and ICDs soon took the ‘wind out of the sails’ from this approach, and studies showing little difference in disability 6-10 years treatment initiation (dopamine agonist versus levodopa monotherapy) also added to the debate. While this remains true, there is potential for P2B001 to change the equation such that the risks of dose-related side-effects, such as somnolence, orthostatic hypotension and hallucinations, are reduced. The combination of rasagiline and low dose pramipexole may provide improved safety and efficacy while reducing motor complications

Within this context, a consistent delay to levodopa and its associated motor complications may be viewed more favorably and studies looking at the delay to motor complications would be warranted. Given its once daily formulation, lack of titration and favorable side-effect profile, P2B001 may be an attractive option for newly diagnosed patients, who often balk at the idea of having to take a medicine three times a day. Moreover, the strategy could also allow lower doses of levodopa to be used once it is introduced. This would also allow a longer period of levodopa utility before motor complications limit the ability to further increase the dose. There is also room for studies of P2B001 as an adjunct to levodopa in patients experiencing motor fluctuations to understand if this ‘dual action’ medication can offer a well-tolerated and convenient alternative to current adjunct medications. Example 4

Prevalence of dopamine related TEAEs by Study Day and Treatment Group

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

Example 5

Prevalence of GI related TEAEs by Study Day and Treatment 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). The temporal profile of 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.

The foregoing description of the specific embodiments will so fully reveal the general nature of the invention that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without undue experimentation and without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. The means, materials, and steps for carrying out various disclosed functions may take a variety of alternative forms without departing from the invention. It is to be understood that further trials are being conducted to establish clinical effects.