WO2013139941A1 - Pharmaceutical combination products for parkinson's disease - Google Patents

Pharmaceutical combination products for parkinson's disease Download PDF

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WO2013139941A1
WO2013139941A1 PCT/EP2013/055993 EP2013055993W WO2013139941A1 WO 2013139941 A1 WO2013139941 A1 WO 2013139941A1 EP 2013055993 W EP2013055993 W EP 2013055993W WO 2013139941 A1 WO2013139941 A1 WO 2013139941A1
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levodopa
parkinson
disease
treatment
dopamine agonist
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PCT/EP2013/055993
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French (fr)
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Charlotte KEYWOOD
Sonia Maria Poli
Mark Wakefield
Mohamad Haitham Ayad
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Addex Pharma S.A.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the present invention relates to a pharmaceutical combination comprising a metabotropic glutamate receptor 5 (mGluRs) negative allosteric modulator and levodopa or a dopamine agonist.
  • the invention also relates to a pharmaceutical combination comprising a metabotropic glutamate receptor 5 (mGluR 5 ) negative allosteric modulator and at least one of a dopa decarboxylase inhibitor or a catechol-O- methyl transferase inhibitor.
  • mGluRs metabotropic glutamate receptor 5
  • levodopa or a dopamine agonist at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor.
  • PD-LID Parkinson's disease levodopa-induced dyskinesia
  • the mGluR 5 negative allosteric modulator will have similar pharmacokinetic parameters to levodopa or to a dopamine agonist.
  • Prolonged levodopa treatment of Parkinson's disease is associated with development of levodopa-induced dyskinesia (LID).
  • LID levodopa-induced dyskinesia
  • the incidence of PD-LID varies according to the age of PD onset, PD duration and progression, levodopa dosage, and the duration of levodopa treatment (Jankovic J. et al. Neuropsychiatr. Dis. Treat. 2008, 4, 743-757; Fabbrini G. et al. Mov. Disord. 2007, 22, 1379-89).
  • Dyskinesias are not solely related to levodopa use, they are also seen following use of dopamine agonists.
  • mGluRs metabotropic glutamate receptor 5
  • MPEP 2-methyl-6-(phenylethynyl)pyridine
  • MTEP 3-[(2-methyl- 1 ,3-thiazol- 4-yl)ethynyl]pyridine
  • mGluR 5 expression was demonstrated to be enhanced in the basal ganglia of Parkinsonian monkeys that developed dyskinesias following chronic levodopa treatment (Samadi P. et al. Neurobiol. Aging, 2008, 29, 1040-5 1 ) and post-mortem brains of Parkinsonian patients with motor complications (Ouattara B. et al. Neurobiol. Aging, 201 1, 32 (7), 1286-95).
  • WO2009/047296 and WO2010/000763 have described that compounds having mGluR 5 antagonistic activity such as AFQ056, may be used to treat PD-LID.
  • AFQ056 may reduce the symptoms of moderate and severe PD-LID in patients without reducing the efficacy of antiparkinsonian therapy.
  • SAE serious adverse events
  • Dipraglurant is the approved name for 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn- 1 - yl]imidazo[ 1 ,2- ]pyridine and is described in WO05123703 (Example 74) as a negative allosteric modulator of the mGluR 5 receptor. Dipraglurant is also known under the reference name ADX48621 (Rocher J.-P. et al. Current Topics in Med. Chem. 201 1 , 11, 680-95). Dipraglurant can exist as salt, co-crystal, solvate, amorphous form or complex with other ingredients.
  • Dipraglurant is a highly soluble and highly permeable molecule (in the Biopharma Classification System, it is a class I compound). This means that after the administration in an immediate release (IR) dosage form, the active substance is rapidly dissolved in the gastrointestinal tract and rapidly absorbed to the systemic circulation. Thus, the duration o exposure is mainly determined by the elimination half-life. Dipraglurant is characterized by an extremely short half-life (ti/ 2 ) of less than 1 hour. A short half-life might be an advantage in certain indications such as for PD-LID. Levodopa is rapidly absorbed and rapidly eliminated and the dyskinesia induced by levodopa tracks the plasma concentration of the drug.
  • an anti-dyskinetic agent will ideally match the levodopa pharmacokinetic profile.
  • coadministration with levodopa requires rapidly a high plasmatic concentration for a short time matching with the pharmacokinetic profile of levodopa.
  • the immediate release formulation of dipraglurant is ideally suited for acute treatment of PD-LID because its pharmacokinetic profile is similar to levodopa by having approximately the same t max and half-life, so the anti-dyskinetic drug is delivered precisely when needed.
  • the rapid onset of action of this formulation is ideal for dyskinesia which can occur within 30 minutes of dosing.
  • the rapid elimination reduces unnecessary drug exposure, between levodopa doses and should reduce side effects as a result.
  • a combination comprising dipraglurant, having similar pharmacokinetic parameters, after oral administration, to levodopa or a dopamine agonist, and at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor not only has a beneficial effect and is useful in the treatment of PD-L1D, but also prevents side effects such as rebound dyskinesia.
  • the present invention relates to combinations, such as a combined pharmaceutical preparation or a pharmaceutical composition, respectively, comprising an mGluR 5 negative allosteric modulator having similar pharmacokinetic parameters to levodopa or a dopamine agonist, and at least one of: i) a dopa decarboxylase inhibitor, or ii) a catechol-O-methyl transferase inhibitor, or in any case a pharmaceutically acceptable salt thereof.
  • the similar pharmacokinetic parameters are t max and half-life.
  • similar pharmacokinetic parameters may mean the substances have a similar plasma concentration vs time profile, for example the substances have similar tmax and half-life values.
  • similar in this context is interpreted in accordance with the understanding of a skilled person.
  • the t ma and/or half-life values of the mGluRs may be the same as, substantially similar to, or approximately the same as, the values for levopoda and/or a dopamine agonist.
  • the mGluR 5 negative allosteric modulator is, for example, dipraglurant.
  • Dopamine agonists are, for example, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole or ropinirole.
  • Dopa decarboxylase inhibitors are, for example, carbidopa or benserazide.
  • Catechol-O-methyl transferase inhibitors are, for example, toltacapone or entacapone.
  • the combination is a pharmaceutical composition or a combined pharmaceutical preparation.
  • the combination partners dipraglurant or a pharmaceutically acceptable salt thereof and levodopa or a dopamine agonist, and at least one of: i) a dopa decarboxylase inhibitor, or ii) a catechol-O-methyl transferase inhibitor, can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms.
  • the unit dosage form may also be a fixed combination.
  • the dosage forms of the combination may not necessarily be of the same dosage form and may comprise one or more type of oral dosage (such as for example capsule, tablet or solution).
  • the invention concerns the use of an mGluRs negative allosteric modulator, dipraglurant, in combination with a second agent for the treatment, prevention and/or delay of progression of Parkinson's dyskinesias, for example, PD- LID.
  • a specific combination is used.
  • Said combination comprises: dipraglurant; and levodopa; and at least one active agent selected from the group consisting of carbidopa, benserazide, toltacapone or entacapone.
  • a specific combination comprises: dipraglurant; and a dopamine agonist; and at least one active agent selected from the group consisting of carbidopa, benserazide, toltacapone or entacapone.
  • a further aspect of the invention relates to a method useful for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an mGluRs negative allosteric modulator in combination with a second agent such as levodopa.
  • Said mGluRs negative allosteric modulator may have similar pharmacokinetic parameters to levodopa; the similar pharmacokinetic parameters may be t max and half-life.
  • the mGluRs negative allosteric modulator may be administered with at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor.
  • the method is for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease, for example, PD-LID or Parkinson's Disease levodopa induced dystonia.
  • a further aspect of the invention relates to a pharmaceutical composition comprising an mGluR 5 negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to levodopa and at least one of: i) a dopa decarboxylase inhibitor; or ii) a catechol-O-methyl transferase inhibitor; or in any case a pharmaceutically acceptable salt thereof; for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease.
  • the similar pharmacokinetic parameters are t max and half-life.
  • the method is for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease, for example, PD-LID or Parkinson's Disease levodopa induced dystonia.
  • a disorder associated with Parkinson's Disease for example, PD-LID or Parkinson's Disease levodopa induced dystonia.
  • a further aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an mGluRs negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to a dopamine agonist and at least one of: i) a dopa decarboxylase inhibitor; or ii) a catechol-O-methyl transferase inhibitor; or in any case a pharmaceutically acceptable salt thereof; for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease.
  • the similar pharmacokinetic parameters are t pitch iax and half-life.
  • the method is for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease, for example, PD-LID or Parkinson's Disease levodopa induced dystonia.
  • a further aspect of the invention relates to the use of an mGluR 5 negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to levodopa and at least one of: i) a dopa decarboxylase inhibitor; or ii) a catechol-O-methyl transferase inhibitor; or in any case a pharmaceutically acceptable salt thereof; for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease.
  • the similar pharmacokinetic parameters are t max and half-life.
  • the method is for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease, for example, PD-LID or Parkinson's Disease levodopa induced dystonia.
  • a disorder associated with Parkinson's Disease for example, PD-LID or Parkinson's Disease levodopa induced dystonia.
  • the agents used in the invention are useful in the treatment, prevention or delay of progression of PD-LID.
  • PD-LID often, although not exclusively, occurs as a side-effect of treatment of Parkinson's disease with levodopa.
  • Characteristics of PD-LID include motor impairment, e.g. the appearance of slow and uncoordinated involuntary movements, shaking, stiffness and problems walking.
  • Patients treated with levodopa often have reduced symptoms of Parkinson's disease but they experience increasing difficulties to remain standing or even sitting. After prolonged use of levodopa, a majority of patients develop dyskinesia. Dyskinesia can occur at any time during the cycle of the treatment with levodopa in parkinsonian patients.
  • the niGluR 5 negative allosteric modulator in combination with other active ingredients as described herein, are for the treatment of dyskinesia which occurs at the time when the levodopa plasma concentrations in the patient rise. Dyskinesia can also develop in Parkinson's disease patients who do not take levodopa. In one embodiment, the combinations are for the treatment of non-levodopa induced Parkinson's dykinesia.
  • Treatment with a mGluR 5 negative allosteric modulator in combination with a second agent such as levodopa or a dopamine agonist and/or at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor may result in a change in the characteristics associated with PD-LID, including for example, but not limited to, a reduction in the scale of involuntary movements, a reduction in the number of involuntary movements, an improvement in the ability to carry out normal tasks, an improved ability to walk, and an increased period of time between episodes of dyskinesia.
  • an immediate release (IR) formulation is suited for the acute treatment of PD-LID, because:
  • the PK characteristics of an I formulation give an advantage of flexibility of dosing in use as a PD treatment.
  • Figure 1 shows human (healthy volunteers) plasma concentration time profiles for 100 mg dipraglurant-IR (black circles) and levodopa (levodopa-carbidopa 100/25 mg formulation - open circles); it can be seen that the plasma concentration time profile of dipraglurant follows that of levodopa;
  • Figure 2 shows mAIMS AUC 0- 3 for dipraglurant IR and placebo for Baseline Day (0) and treatment Days 1 (50mg), 14 and 28 (lOOmg);
  • Figure 3 shows Peak mAlMs score change from baseline on Treatment Days 1 , 14 and 28 (FAS population);
  • Figure 4 shows Patient diary data. Percentage of time in "on” with no dyskinesia, change from pre-treatment Week 1 , for Treatment Weeks 1 , 2, 3 and 4;
  • Figure 5 shows Peak mAIMS dystonia score (90 min) at baseline (Day 0) and on Treatment Days 1, 14 and 28 (FAS population).
  • Dipraglurant phosphate API 68.50 Corresponding to dipraglurant free base (50.00)
  • the Gelucire® formulation was developed in order to match the peak in dipraglurant plasma concentration observed after administration of the simple immediate-release (IR) drug substance filled capsules with the peak of levodopa concentration. Additionally, it showed a very similar pharmacokinetic profile to levodopa. This formulation is chosen for this Phase II study as it offers an optimal P profile for the evaluation of the clinical efficacy of dipraglurant-IR in acute treatment of PD-LID.
  • Gelucire* is molten and maintained at a temperature around 55°C during all the process.
  • the API is then added slowly to the molten Gelucire, under effective homogenization, until a homogeneous suspension is obtained.
  • the mixture is transferred to the jacketed vessel of the filling machine.
  • the capsule filling is performed using automated filling machine and the In Process Controls are performed during the filling process to verify the quality of the filled capsules.
  • Parkinsonian dyskinesias fall into three types. The most common are peak dose dyskinesias which occur at maximum levodopa plasma concentration, 60-90 mins post- dose. Biphasic dyskinesia, occurs at the beginning and end of "On" time around 30 mins and 120 to 150 mins post levodopa dose. The third, less common type, is "Off" dystonia, which occurs once levodopa has worn off.
  • the immediate release (IR) formulation of dipraglurant is ideal for the acute treatment of PD-LID, because the plasma concentration vs time profile closely parallels that of levodopa, with peak plasma concentration occurring around the same time (t max ) as that of levodopa and the duration of plasma concentration covering the "On" period.
  • Example 1 Assessment of the anti-dyskinetic effect of dipraglurant-IR in combination with levodopa in human patients
  • the study was a multicentre, randomised double-blind, placebo-controlled, outpatient study for PD patients with moderate to severe LID on stable dopaminergic (levodopa 300-1500 mg/day) therapy.
  • the study treatment period was 4 weeks during which time patients followed a dose escalation regimen from 50 mg (or placebo) once daily, through to 100 mg (or placebo) three times daily.
  • 50 mg or placebo
  • placebo placebo
  • Dipraglurant-IR or placebo was taken in conjunction with the patients' regular doses of levodopa which caused troublesome dyskinesia.
  • the timing of which levodopa doses were co-administered with the study medication was fixed for the 4 week study period, at the initial screening visit and was tailored to each individual patient according to his need.
  • dyskinesia was "provoked” by asking the patients to subtract serial 7's from 100. Every 30 minutes for 3 hours following levodopa dosing, 7 body areas were scored with scores from 0 (none) to 4 (severe). Face, neck, R arm, L arm, trunk, R leg, L leg for a total of 28 points per 30 min time point. From these 6 time points, a time course curve could be constructed for each test (see Figure 1).
  • Each mAIMS test was done following the patient's regular "middle of the day" levodopa dose identified at screening. The same dose was used for all assessments which were performed on: ⁇ Day 0 before treatment i.e. levodopa alone
  • Dyskinesia and motor fluctuations were also evaluated in patient diaries. Patients collected data in diaries for 48 hours at the end of every week from Week -1 to Treatment Week 4.
  • Dipraglurant-IR in combination with levodopa thus showed a clinically relevant and significant anti-dyskinetic effect without changing the anti-Parkinsonian effects of levodopa therapy.

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Abstract

The present invention relates in one embodiment to a pharmaceutical combination of a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator and levodopa or a dopamine agonist, and at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor for the treatment of PD-LID. In this exemplary pharmaceutical combination, the mGluR5 negative allosteric modulator will have similar pharmacokinetic parameters to levodopa or to a dopamine agonist.

Description

PHARMACEUTICAL COMBINATION PRODUCTS FOR PARKINSON'S
DISEASE
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical combination comprising a metabotropic glutamate receptor 5 (mGluRs) negative allosteric modulator and levodopa or a dopamine agonist. The invention also relates to a pharmaceutical combination comprising a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator and at least one of a dopa decarboxylase inhibitor or a catechol-O- methyl transferase inhibitor. These may be in the form of a pharmaceutical combination comprising a metabotropic glutamate receptor 5 (mGluRs) negative allosteric modulator, and levodopa or a dopamine agonist, and at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor. These combinations are useful for the treatment of Parkinson's disease levodopa-induced dyskinesia (PD-LID). In the pharmaceutical combinations, the mGluR5 negative allosteric modulator will have similar pharmacokinetic parameters to levodopa or to a dopamine agonist.
BACKGROUND TO THE INVENTION
Prolonged levodopa treatment of Parkinson's disease (PD) is associated with development of levodopa-induced dyskinesia (LID). The incidence of PD-LID varies according to the age of PD onset, PD duration and progression, levodopa dosage, and the duration of levodopa treatment (Jankovic J. et al. Neuropsychiatr. Dis. Treat. 2008, 4, 743-757; Fabbrini G. et al. Mov. Disord. 2007, 22, 1379-89). Dyskinesias are not solely related to levodopa use, they are also seen following use of dopamine agonists.
Current approaches to reducing PD-LID such as administering dopamine agonists, altering levodopa dosage, formulation or frequency, and use of the antiglutamatergic drag amantadine do not provide long-term effectiveness. Deep brain stimulation has been shown to reduce PD-LID but is not suitable for all patients, is costly and time consuming, and has risks of complications including hemorrhage and hardware problems (Groiss et al. Ther. Adv. Neurol. Disord. 2009, 2, 379-91 ).
The development of PD-LID has been associated with glutamatergic hyperactivity in the basal ganglia (Gomez-Mancilla B. et al. Clin. Neuropharmacol. 1993, 16, 418-27; Chase T. N. et al. Trends Neurosci. 2000, 23 ( 10), 586-91). The action of glutamate is mediated through a family of eight G-protein coupled receptors that have been found to modulate presynaptic neurotransmitter release and the post-synaptic activity of ionotropic glutamate receptors (Meldrum B. S. J. Nutr. 2000, 130, 1007S-15S). Among these receptors, the high striatal expression of metabotropic glutamate receptor 5 (mGluRs) suggests a role for mGluR5 antagonists in movemement disorders. Pharmacological antagonism of mGluR5 with the mGluRs negative allosteric modulators 2-methyl-6-(phenylethynyl)pyridine (MPEP) and 3-[(2-methyl- 1 ,3-thiazol- 4-yl)ethynyl]pyridine (MTEP) was shown to inhibit expression of dyskinesias in rodent (Mela F. J. Neurochem. 2007, 101 , 483-497) and primate models (Johnston T. H. et al. J. Pharmacol. Exp. Therapeut. 2010, 333, 865-73; Morin N. et al., Neuropharmacology, 2010, 58, 981-6) of Parkinson's disease. Moreover, mGluR5 expression was demonstrated to be enhanced in the basal ganglia of Parkinsonian monkeys that developed dyskinesias following chronic levodopa treatment (Samadi P. et al. Neurobiol. Aging, 2008, 29, 1040-5 1 ) and post-mortem brains of Parkinsonian patients with motor complications (Ouattara B. et al. Neurobiol. Aging, 201 1, 32 (7), 1286-95).
WO2009/047296 and WO2010/000763 have described that compounds having mGluR5 antagonistic activity such as AFQ056, may be used to treat PD-LID. Berg. D. et al. have shown in Mov. Disord. 201 1, 26(7), 1243-50 that AFQ056 may reduce the symptoms of moderate and severe PD-LID in patients without reducing the efficacy of antiparkinsonian therapy. During these studies, the most common serious adverse events (SAE) was worsening of dyskinesias and was apparently associated with stopping treatment. it has now been surprisingly found that the use of a combination comprising an mGluRs negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to levodopa or a dopamine agonist and at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor has a beneficial effect and is useful in the treatment of PD-LID.
Dipraglurant is the approved name for 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn- 1 - yl]imidazo[ 1 ,2- ]pyridine and is described in WO05123703 (Example 74) as a negative allosteric modulator of the mGluR5 receptor. Dipraglurant is also known under the reference name ADX48621 (Rocher J.-P. et al. Current Topics in Med. Chem. 201 1 , 11, 680-95). Dipraglurant can exist as salt, co-crystal, solvate, amorphous form or complex with other ingredients. Dipraglurant is a highly soluble and highly permeable molecule (in the Biopharma Classification System, it is a class I compound). This means that after the administration in an immediate release (IR) dosage form, the active substance is rapidly dissolved in the gastrointestinal tract and rapidly absorbed to the systemic circulation. Thus, the duration o exposure is mainly determined by the elimination half-life. Dipraglurant is characterized by an extremely short half-life (ti/2) of less than 1 hour. A short half-life might be an advantage in certain indications such as for PD-LID. Levodopa is rapidly absorbed and rapidly eliminated and the dyskinesia induced by levodopa tracks the plasma concentration of the drug. To be efficient in reversing LID, an anti-dyskinetic agent will ideally match the levodopa pharmacokinetic profile. Thus, coadministration with levodopa requires rapidly a high plasmatic concentration for a short time matching with the pharmacokinetic profile of levodopa.
The immediate release formulation of dipraglurant is ideally suited for acute treatment of PD-LID because its pharmacokinetic profile is similar to levodopa by having approximately the same tmax and half-life, so the anti-dyskinetic drug is delivered precisely when needed. The rapid onset of action of this formulation, is ideal for dyskinesia which can occur within 30 minutes of dosing. The rapid elimination reduces unnecessary drug exposure, between levodopa doses and should reduce side effects as a result.
It has now been surprisingly found that the use of a combination comprising dipraglurant, having similar pharmacokinetic parameters, after oral administration, to levodopa or a dopamine agonist, and at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor not only has a beneficial effect and is useful in the treatment of PD-L1D, but also prevents side effects such as rebound dyskinesia.
Thus the present invention relates to combinations, such as a combined pharmaceutical preparation or a pharmaceutical composition, respectively, comprising an mGluR5 negative allosteric modulator having similar pharmacokinetic parameters to levodopa or a dopamine agonist, and at least one of: i) a dopa decarboxylase inhibitor, or ii) a catechol-O-methyl transferase inhibitor, or in any case a pharmaceutically acceptable salt thereof. The similar pharmacokinetic parameters are tmax and half-life.
The term "similar pharmacokinetic parameters" may mean the substances have a similar plasma concentration vs time profile, for example the substances have similar tmax and half-life values. The term "similar" in this context is interpreted in accordance with the understanding of a skilled person. The tma and/or half-life values of the mGluRs may be the same as, substantially similar to, or approximately the same as, the values for levopoda and/or a dopamine agonist.
The mGluR5 negative allosteric modulator is, for example, dipraglurant.
Dopamine agonists are, for example, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole or ropinirole.
Dopa decarboxylase inhibitors are, for example, carbidopa or benserazide. Catechol-O-methyl transferase inhibitors are, for example, toltacapone or entacapone.
Preferably the combination is a pharmaceutical composition or a combined pharmaceutical preparation.
In this pharmaceutical composition, the combination partners dipraglurant or a pharmaceutically acceptable salt thereof and levodopa or a dopamine agonist, and at least one of: i) a dopa decarboxylase inhibitor, or ii) a catechol-O-methyl transferase inhibitor, can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a fixed combination.
As used herein the term "Use of a combination for treatment of..." is interchangeable with the term "Combination for use in the treatment of....". As used herein, the term "combinations" shall be taken to mean one or more substances which can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms.
Administration of the dosage forms may be concomitantly, simultaneously, part- simultaneously or separately. The dosage forms of the combination may not necessarily be of the same dosage form and may comprise one or more type of oral dosage (such as for example capsule, tablet or solution).
In one embodiment, the invention concerns the use of an mGluRs negative allosteric modulator, dipraglurant, in combination with a second agent for the treatment, prevention and/or delay of progression of Parkinson's dyskinesias, for example, PD- LID. in one embodiment of the invention a specific combination is used. Said combination comprises: dipraglurant; and levodopa; and at least one active agent selected from the group consisting of carbidopa, benserazide, toltacapone or entacapone.
In one embodiment of the invention a specific combination is used. Said combination comprises: dipraglurant; and a dopamine agonist; and at least one active agent selected from the group consisting of carbidopa, benserazide, toltacapone or entacapone.
A further aspect of the invention relates to a method useful for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an mGluRs negative allosteric modulator in combination with a second agent such as levodopa. Said mGluRs negative allosteric modulator may have similar pharmacokinetic parameters to levodopa; the similar pharmacokinetic parameters may be tmax and half-life. The mGluRs negative allosteric modulator may be administered with at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor.
In one embodiment, the method is for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease, for example, PD-LID or Parkinson's Disease levodopa induced dystonia. A further aspect of the invention relates to a pharmaceutical composition comprising an mGluR5 negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to levodopa and at least one of: i) a dopa decarboxylase inhibitor; or ii) a catechol-O-methyl transferase inhibitor; or in any case a pharmaceutically acceptable salt thereof; for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease. The similar pharmacokinetic parameters are tmax and half-life.
In one embodiment, the method is for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease, for example, PD-LID or Parkinson's Disease levodopa induced dystonia.
A further aspect of the invention relates to a pharmaceutical composition comprising an mGluRs negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to a dopamine agonist and at least one of: i) a dopa decarboxylase inhibitor; or ii) a catechol-O-methyl transferase inhibitor; or in any case a pharmaceutically acceptable salt thereof; for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease. The similar pharmacokinetic parameters are t„iax and half-life.
In one embodiment, the method is for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease, for example, PD-LID or Parkinson's Disease levodopa induced dystonia. A further aspect of the invention relates to the use of an mGluR5 negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to levodopa and at least one of: i) a dopa decarboxylase inhibitor; or ii) a catechol-O-methyl transferase inhibitor; or in any case a pharmaceutically acceptable salt thereof; for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease. The similar pharmacokinetic parameters are tmax and half-life.
In one embodiment, the method is for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease, for example, PD-LID or Parkinson's Disease levodopa induced dystonia.
The agents used in the invention, especially modulators of mGluR5 receptors, are useful in the treatment, prevention or delay of progression of PD-LID. PD-LID often, although not exclusively, occurs as a side-effect of treatment of Parkinson's disease with levodopa. Characteristics of PD-LID include motor impairment, e.g. the appearance of slow and uncoordinated involuntary movements, shaking, stiffness and problems walking. Patients treated with levodopa often have reduced symptoms of Parkinson's disease but they experience increasing difficulties to remain standing or even sitting. After prolonged use of levodopa, a majority of patients develop dyskinesia. Dyskinesia can occur at any time during the cycle of the treatment with levodopa in parkinsonian patients.
In one embodiment, the niGluR5 negative allosteric modulator, in combination with other active ingredients as described herein, are for the treatment of dyskinesia which occurs at the time when the levodopa plasma concentrations in the patient rise. Dyskinesia can also develop in Parkinson's disease patients who do not take levodopa. In one embodiment, the combinations are for the treatment of non-levodopa induced Parkinson's dykinesia.
Treatment with a mGluR5 negative allosteric modulator in combination with a second agent such as levodopa or a dopamine agonist and/or at least one of a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor may result in a change in the characteristics associated with PD-LID, including for example, but not limited to, a reduction in the scale of involuntary movements, a reduction in the number of involuntary movements, an improvement in the ability to carry out normal tasks, an improved ability to walk, and an increased period of time between episodes of dyskinesia.
According to another aspect of the invention, an immediate release (IR) formulation is suited for the acute treatment of PD-LID, because:
-Its pharmacokinetic profile is similar to levadopa, so the drug is delivered precisely when needed;
-Its rapid onset of action suits treatment o dyskinesia which can occur within 30 minutes of dosing with levadopa; -The rapid clearance reduces unnecessary drug exposure between levodopa doses, and can reduce side-effects as a result; and
-The PK characteristics of an I formulation give an advantage of flexibility of dosing in use as a PD treatment.
The full extent of the present invention is further defined by the attached claims. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows human (healthy volunteers) plasma concentration time profiles for 100 mg dipraglurant-IR (black circles) and levodopa (levodopa-carbidopa 100/25 mg formulation - open circles); it can be seen that the plasma concentration time profile of dipraglurant follows that of levodopa;
Figure 2 shows mAIMS AUC0-3 for dipraglurant IR and placebo for Baseline Day (0) and treatment Days 1 (50mg), 14 and 28 (lOOmg);
Figure 3 shows Peak mAlMs score change from baseline on Treatment Days 1 , 14 and 28 (FAS population);
Figure 4 shows Patient diary data. Percentage of time in "on" with no dyskinesia, change from pre-treatment Week 1 , for Treatment Weeks 1 , 2, 3 and 4;
Figure 5 shows Peak mAIMS dystonia score (90 min) at baseline (Day 0) and on Treatment Days 1, 14 and 28 (FAS population).
DETAILED DESCRIPTION OF THE INVENTION Formulation
Qualitative composition of dipraglurant capsules:
Quantity
Ingredient Function
mg/cps
Dipraglurant phosphate API 68.50 (Corresponding to dipraglurant free base) (50.00)
Lauroyl macrogol glyceride 1500 Lipid base excipient 251.50 (Gelucire* 44/14)
Total 320.00 The Gelucire® formulation was developed in order to match the peak in dipraglurant plasma concentration observed after administration of the simple immediate-release (IR) drug substance filled capsules with the peak of levodopa concentration. Additionally, it showed a very similar pharmacokinetic profile to levodopa. This formulation is chosen for this Phase II study as it offers an optimal P profile for the evaluation of the clinical efficacy of dipraglurant-IR in acute treatment of PD-LID.
Preparation of dipraglurant-IR capsules: Gelucire* is molten and maintained at a temperature around 55°C during all the process. The API is then added slowly to the molten Gelucire, under effective homogenization, until a homogeneous suspension is obtained. The mixture is transferred to the jacketed vessel of the filling machine. The capsule filling is performed using automated filling machine and the In Process Controls are performed during the filling process to verify the quality of the filled capsules.
Pharmacokinetic profile
Parkinsonian dyskinesias fall into three types. The most common are peak dose dyskinesias which occur at maximum levodopa plasma concentration, 60-90 mins post- dose. Biphasic dyskinesia, occurs at the beginning and end of "On" time around 30 mins and 120 to 150 mins post levodopa dose. The third, less common type, is "Off" dystonia, which occurs once levodopa has worn off.
The immediate release (IR) formulation of dipraglurant is ideal for the acute treatment of PD-LID, because the plasma concentration vs time profile closely parallels that of levodopa, with peak plasma concentration occurring around the same time (tmax) as that of levodopa and the duration of plasma concentration covering the "On" period.
In Figure 1 , human (healthy volunteers) plasma concentration time profiles were shown for 100 mg of dipraglurant-IR (black circles) and levodopa (levodopa-carbidopa 100/25 mg formulation - open circles). It can be seen how the plasma concentration vs time profile of dipraglurant follows that of levodopa. The rapid absorption of dipraglurant-IR means effective plasma concentrations will be achieved when most needed, i.e. at peak levodopa plasma concentrations. In addition, the short half life of the compound gives the advantage of a complete wash out of the drug between doses, avoiding drug accumulation, rebound effects and also side effects resulting from high, constant drug levels, which are not needed to control PD-LID.
Clinical design
Example 1 : Assessment of the anti-dyskinetic effect of dipraglurant-IR in combination with levodopa in human patients
Method:
The study was a multicentre, randomised double-blind, placebo-controlled, outpatient study for PD patients with moderate to severe LID on stable dopaminergic (levodopa 300-1500 mg/day) therapy. The study treatment period was 4 weeks during which time patients followed a dose escalation regimen from 50 mg (or placebo) once daily, through to 100 mg (or placebo) three times daily. Of 76 randomized patients, 52 received dipraglurant-IR and 24 received placebo. Dipraglurant-IR or placebo was taken in conjunction with the patients' regular doses of levodopa which caused troublesome dyskinesia. The timing of which levodopa doses were co-administered with the study medication was fixed for the 4 week study period, at the initial screening visit and was tailored to each individual patient according to his need.
Assessment: Safety and tolerability were evaluated with measurements of heart rate, blood pressure, 12-lead ECG, blood testing for haematology and biochemistry and adverse events enquiry. Dyskinesia was evaluated in the clinic by trained observers using the modified abnormal involuntary movement scale (mAIMS) and by patient reported outcome in diaries.
Results:
For the mAIMS test, dyskinesia was "provoked" by asking the patients to subtract serial 7's from 100. Every 30 minutes for 3 hours following levodopa dosing, 7 body areas were scored with scores from 0 (none) to 4 (severe). Face, neck, R arm, L arm, trunk, R leg, L leg for a total of 28 points per 30 min time point. From these 6 time points, a time course curve could be constructed for each test (see Figure 1).
Each mAIMS test was done following the patient's regular "middle of the day" levodopa dose identified at screening. The same dose was used for all assessments which were performed on: · Day 0 before treatment i.e. levodopa alone
• Day 1 levodopa + 50 mg d i pragl urant/p 1 acebo - (first ever dose of study drug)
• Day 14 levodopa + 100 mg dipraglurant/placebo - (first dose of l OOmg/placebo)
• Day 28 levodopa + 100 mg dipraglurant/placebo The study design targeted a 30% percentage reduction in mAIMS area under the curve (AUC0-3) for dipraglurant versus a 10% reduction in the placebo group, compared to the levodopa alone curve obtained at baseline Day 0.
The time course of dyskinesia followed the pharmacokinetics of levodopa, with peak dyskinesia occurring at peak plasma concentrations of levodopa, ie. around 90 minutes post dose. Administration of dipraglurant-IR blunted the curve and reduced peak dose mAIMS. The target reduction in levodopa-induced dyskinesia severity over the 3 hour post dose period was achieved for the dipraglurant group at Day 14 (32.7%) and Day 28 (27.5%) The reduction in AIMS AUC0-3 in the dipraglurant 1 OOmg group was statistically significant at Day 14 (p = 0.042 ANCOVA). No statistical significance at Day 28 (p = 0.48). On Day 1 , dipraglurant 50 nig reduced mAIMS AUC0.3 by 17.9% (placebo 1 1.7%)
A more pronounced effect was seen for peak dose mAIMS score (see Figure 2). At Baseline (Day 0) mAIMS values were 12.0 for dipraglurant-IR and 12.25 for placebo. The mAIMS at peak dose levodopa was significantly lower on Days 1 and 14; with the percentage reduction for dipraglurant as follows:
• Day 1 : 19.9% vs 4.1% (placebo) p = 0.042 · Day 14: 32.3% vs 12.6% (placebo) p = 0.034
• Day 28: 31.4% vs 21.5% (placebo) p = ns
Dyskinesia and motor fluctuations were also evaluated in patient diaries. Patients collected data in diaries for 48 hours at the end of every week from Week -1 to Treatment Week 4.
• At the end of treatment Week 1 , dose 50 mg b.d (midday and evening).
• End of Week 2 dose 50 mg t.i.d
• End of Week 3 dose 50 mg am, 100 mg midday, 100 mg evening and 2 patients were taking dipraglurant 50 mg.
• End of Week 4 patients took 100 mg t.i.d.
Every 30 minutes the patient marked whether they were asleep, in "off", in "on" with no dyskinesia, in "on" with non troublesome dyskinesia or in "on" with troublesome dyskinesia.
From the diary data no increase in "off' time was seen with dipraglurant-IR use. At week 4 "off time actually decreased by 50 minutes per day in the dipraglurant-IR group. Their amount of time in "on" with no dyskinesia increased to a greater extent on all 4 weeks compared to placebo. By week 4 patients in the dipraglurant-IR group had an extra 2.3 hours per day "on" time with no dyskinesia. Both the 50 and 100 mg doses increased "on" time with no dyskinesia.
At Week - 1 the percentage of "on" time with no dyskinesia was 19.25% (4.6 hours) in the dipraglurant-IR group and 22.22% (5.3 hours) in the placebo group. In the Dipraglurant-IR group "on" time with no dyskinesia increased by 1.25, 1.8, 2.0 and 2.3 hours per day in Weeks 1 , 2, 3 and 4 (placebo increase 0.6, 1.2, 0.9 and 1.7 hours per day).
This study of dipraglurant-IR in Parkinson's patients has demonstrated good safety and tolerability. Exploratory efficacy data showed anti-dyskinetic effect on both observer evaluated mAIMS and in patient reported diary data. The magnitude of effect on mAIMS (circa 30%) was as predicted on Days 14 and 28, as was placebo (circa 10 - 15%) on Days 1 and 14. Both the 50 and 1 OOmg doses showed anti-dyskinetic effect. There was a suggestion of beneficial effect on motor fluctuations from patient diaries, which warrants further investigation. Limited data (mAIMS highest score) in dystonia patients (n = 7) showed the same pattern of effect as in the overall full analysis set (FAS) population, suggesting that dipraglurant-IR is also effective in reducing the severity of levodopa induced dystonia as illustrated in Figure 5.
During the study, no rebound dyskinesia has been reported after the end of treatment with dipraglurant-IR.
Dipraglurant-IR in combination with levodopa thus showed a clinically relevant and significant anti-dyskinetic effect without changing the anti-Parkinsonian effects of levodopa therapy. This supports the use of an mGluR5 negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to levodopa or a dopamine agonist for the treatment of PD-LID with a better tolerability.

Claims

1 . Use of an mGluRs negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to levodopa and/or a dopamine agonist, and at least one of: i) a dopa decarboxylase inhibitor; or ii) a catechol-O-methyl transferase inhibitor; or in any case a pharmaceutically acceptable salt thereof; for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease; wherein the similar pharmacokinetic parameters are the tmax and the half-life.
2. Use according to claim 1 , wherein the mGluR5 negative allosteric modulator is dipraglurant or a pharmaceutically acceptable salt thereof.
3. Use according to any preceding claim, wherein the dopa decarboxylase inhibitor is carbidopa or benserazide.
Use according to any preceding claim, wherein the catechol-O-methyl transferase inhibitor is tolcapone or entacapone.
Use according to any preceding claim, wherein the dopamine agonist is apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole or ropinirole.
6. Use according to any preceding claim, wherein the disorder is Parkinson's Disease levodopa induced dyskinesia.
7. Use according to any preceding claim, wherein the disorder is Parkinson's Disease non levodopa induced dyskinesia.
8. Use according to any preceding claim, wherein the disorder is Parkinson's Disease levodopa induced dystonia.
9. Use according to any preceding claim, which additionally uses levodopa or a dopamine agonist.
10. A method useful for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an mGluR5 negative allosteric modulator and at least one of: i) a dopa decarboxylase inhibitor; or
ii) a catechol-O-methyl transferase inhibitor; in combination with a second agent which is levodopa or a dopamine agonist; wherein the mGluRs negative allosteric modulator has similar pharmacokinetic parameters, after oral administration, to levodopa and/or a dopamine agonist; and wherein the similar pharmacokinetic parameters are the tmax and the half- life.
1 1. A method useful for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount o dipraglurant and at least one of: i) a dopa decarboxylase inhibitor; or
ii) a catechol-O-methyl transferase inhibitor; in combination with a second agent which is levodopa.
12. A method useful for treating, preventing or delaying the progression of Parkinson's disease and/or a disorder associated with Parkinson's Disease in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of dipraglurant and at least one of: i) a dopa decarboxylase inhibitor; or
ii) a catechol-O-methyl transferase inhibitor; in combination with a second agent which is a dopamine agonist.
13. A method according to claims 10 to 12, wherein the disorder is as as defined claims 6, 7 or 8.
14. A method according to claims 10 to 12, wherein the dopa decarboxylase inhibitor and the catechol-Q-methyi transferase inhibitor are as defined in claims 3 and 4.
15. A method according to claim 10 or 12, wherein the dopamine agonist is as defined in claim 5.
16. A combination comprising an mGluR5 negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to levodopa and/or a dopamine agonist, and at least one of: i) a dopa decarboxylase inhibitor; or ii) a catechol-O-methyl transferase inhibitor; or in any case a pharmaceutically acceptable salt thereof; for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease; wherein the similar pharmacokinetic parameters are the tmax and the half-life.
17. The combination of claim 16, wherein the mGluR.5 negative allosteric modulator is dipraglurant or in any case a pharmaceutically acceptable salt thereof.
18. The combination of claims 16 or 17, wherein the dopa decarboxylase inhibitor and the catechol-O-methyl transferase inhibitor are as defined in claims 3 and 4.
19. The combination of any of claims 16 to 18, which additionally comprises levodopa or a dopamine agonist.
20. The combination of any of claims 16 to 19, wherein the dopamine agonist is as defined in claim 5.
21. The combination of any of claims 16 to 20, wherein the disorder is as as defined in claims 6, 7 or 8.
22. A pharmaceutical composition comprising an mGluRs negative allosteric modulator having similar pharmacokinetic parameters, after oral administration, to levodopa and/or a dopamine agonist, and at least one of: i) a dopa decarboxylase inhibitor; or ii) a catechol-O-methyl transferase inhibitor; or in any case a pharmaceutically acceptable salt thereof; for the treatment, prevention or delay of progression of Parkinson's Disease and/or a disorder associated with Parkinson's Disease; wherein the similar pharmacokinetic parameters are the tmax and the half-life.
23. A pharmaceutical composition according to claim 22, wherein the disorder is as as defined in claims 6, 7 or 8.
24. The pharmaceutical composition of claims 22 or 23, wherein the mGluR5 negative allosteric modulator is dipraglurant or in any case a pharmaceutically acceptable salt thereof.
25. The pharmaceutical composition of claims 22 to 24, wherein the dopa decarboxylase inhibitor and the catechol-O-methyl transferase inhibitor are as defined in claims 3 and 4.
26. The pharmaceutical composition according to any of claims 22 to 25 which additionally comprises levodopa or a dopamine agonist.
27. A kit comprising i) an amount of an mGluR5 negative allosteric modulator or a pharmaceutically acceptable salt thereof in a first unit dosage form; and ii) an amount of at least one active ingredient selected from levodopa or a dopamine agonist; and iii) an amount of at least one active ingredient selected from a dopa decarboxylase inhibitor or a catechol-O-methyl transferase inhibitor; and iv) a container for containing said first, second, third, etc unit forms; and v) instructions for using the combination of ingredients in the treatment, prevention or delay of progression of Parkinson's disease and/or a disorder associated with Parkinson's disease; wherein the niGluR.5 negative allosteric modulator has similar pharmacokinetic parameters, after oral administration, to levodopa or a dopamine agonist; and wherein the similar pharmacokinetic parameters are the tmax and the half-life.
28. A kit according to claim 27, wherein the mGluR5 negative allosteric modulator is dipraglurant or in any case a pharmaceutically acceptable salt thereof.
29. A kit according to claims 27 or 28, wherein the disorder is as as defined in claims 6, 7 or 8.
30. A Use, Method, Combination, Composition or Kit according to any preceding claim, wherein the treatment is treatment of PD-LID by immediate release (IR) formulation of active ingredients.
3 1. A Use, Method, Combination, Composition or Kit according to any preceding claim, wherein the treatment is treatment by co-administration of active ingredients.
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WO2015044270A1 (en) * 2013-09-25 2015-04-02 Addex Pharma S.A. Mono-phosphate salt of 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl]imidazo[1,2a]pyridine and polymorphs thereof as negative allosteric modulator of mglu5 receptor
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AU2014327236B2 (en) * 2013-09-25 2018-03-22 Addex Pharma S.A. Mono-phosphate salt of 6-fluoro-2-[4-(pyridin-2-yl)but-3-yn-1-yl]imidazo[1,2a]pyridine and polymorphs thereof as negative allosteric modulator of mGlu5 receptor
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