Treatment of primary progressive multiple sclerosis

Abstract

The present invention provides compositions and methods of use thereof for treating or ameliorating primary progressive multiple sclerosis by intramuscular administration of a depot formulation comprising 25 mg glatiramer acetate every 2-6 weeks.

Description

[0001] TREATMENT OF PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to methods of treating primary progressive multiple sclerosis (PPMS) using a depot formulation of glatiramer or a pharmaceutically acceptable salt thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) which typically occurs at young adults, more prevalent in women than in men. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other and control body functions. The clinical disability is linked to an inflammation of myelin, the protective sheath around the axons of the CNS, which is damaged due to an autoimmune attack and neurodegenerative processes. As a consequence, the white matter of the brain and spinal cord becomes scarred by focal lesions (plaques) leading to neurological dysfunction.

[0006] There are several patterns of symptoms of MS. Most patients experience a relapsing-remitting (RRMS) course at the initial stage, characterized by unpredictable relapses followed by periods of partial or complete recovery (remission), which at some point becomes progressive (PMS). Such progressive MS is classified as secondary progressive MS (SPMS). Some patients experience a progressive course from the onset of symptoms, and such disease pattern is classified as primary progressive MS (PPMS). PPMS is characterized by a continuous decline in neurological function starting from the initial symptoms, without early relapses or remissions. Approximately 10-15% of MS patients are diagnosed as having PPMS at onset.

[0007] Copolymer-1, also known as glatiramer acetate (GA) and marketed under the tradename Copaxone®, comprises the acetate salt of a mixture of random synthetic copolymers of L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is 5,000-9,000 Da and it is indicated for the reduction of the frequency of relapses in patients with RRMS. Although glatiramer acetate (Copaxone®) has been approved over 25 years ago for treating RRMS, the first drug to treat PPMS is Ocrelizumab (Ocrevus™) which is a humanized anti-CD20 monoclonal antibody that was approved by the FDA in 2017.

[0008] Ziemssen et al. (PLOS ONE | DOI: 10.1371 / journal. pone.0138243, 2015) reports a systematic review of 52 PPMS studies and concludes that the lack of evidence for efficacy in the treatment of PPMS patients stems from fundamental differences between PPMS and relapsing or secondary-progressive disease courses. According to this reference, drugs assessed to date may not target the pathology of PPMS or may simply be unable to cross the blood-brain barrier.

[0009] U.S 8,377,885 discloses a long-acting parenteral pharmaceutical composition comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, the composition being in a sustained release depot form which releases a therapeutically effective amount of the pharmaceutically acceptable salt of glatiramer over a period of about one week to about 6 months.

[0010] WO 2018 / 178973 discloses a method of treating or alleviating primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS) or a symptom thereof in a patient diagnosed with PPMS or SPMS, the method comprising the step of administering or implanting a sustained release depot formulation comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer to the patient.

[0011] To date, no glatiramer acetate treatment for PPMS patients has been approved. There is an unmet medical need for developing new treatment modalities for PPMS patients.

[0012] SUMMARY OF THE INVENTION

[0013] The present invention provides compositions and methods for treating primary progressive multiple sclerosis (PPMS), comprising a single parenteral administration of a long-acting depot composition containing 25 mg of a pharmaceutically acceptable salt of glatiramer, in particular glatiramer acetate (GA), once every 2-6 weeks. The present invention is based, in part, on the unexpected finding that not only did a dose of 25 mg GA depot formulation once every 28 days resulted in a lower rate of adverse events and injection site reactions as compared to a 40 mg dose administered at the same frequency, it also showed at least a comparable therapeutic effect to a 40 mg dose. In particular, despite cutting the dose of 40 mg GA almost in half to a dose of 25 mg, the therapeutic efficacy was either maintained or elevated. In addition, the data demonstrated a clear trend in favor of the 25 mg dose in terms of both safety and tolerability.

[0014] According to a first aspect, there is provided a method of treating a subject afflicted with primary progressive multiple sclerosis (PPMS), the method comprising administering to the subject a therapeutically effective regimen of a single intramuscular injection of a depot formulation comprising a 25 mg dose of glatiramer acetate (GA) every 2 to 6 weeks.

[0015] According to a second aspect, there is provided a depot formulation comprising a 25 mg dose of glatiramer acetate (GA) for use in treating a subject afflicted with primary progressive multiple sclerosis (PPMS), wherein the formulation is adapted for a therapeutically effective regimen of a single intramuscular injection every 2 to 6 weeks.

[0016] According to a third aspect, there is provided the use of a depot formulation comprising a 25 mg dose of glatiramer acetate (GA) for the preparation of a medicament for treating a subject afflicted with primary progressive multiple sclerosis (PPMS), wherein the formulation is adapted for a therapeutically effective regimen of a single intramuscular injection every 2 to 6 weeks.

[0017] In some embodiments, the depot formulation is adapted for administration once every 3 to 5 weeks. In certain embodiments, the depot formulation is adapted for administration once every 4 weeks.

[0018] In various embodiments, treating a subject afflicted with PPMS comprises reducing the rate of progression of PPMS. In other embodiments, treating a subject afflicted with PPMS comprises increasing the time to onset of Confirmed Disease Progression (CDP). In yet other embodiments, treating a subject afflicted with PPMS comprises increasing the time to onset of 12 week Confirmed Disease Progression (CDP) assessed by EDSS, compared to baseline. In further embodiments, treating a subject afflicted with PPMS comprises decreasing whole brain volume change or cortical volume change, compared to baseline. In additional embodiments, treating a subject afflicted with PPMS comprises decreasing the time needed to complete a timed 25-foot walk (T25FW) test, compared to baseline. In particular embodiments, treating a subject afflicted with PPMS comprises decreasing the time needed to complete a 9- Hole Peg Test (9-HPT), compared to baseline.

[0019] In specific embodiments, treating a subject afflicted with PPMS comprises maintaining a substantially constant EDSS score. In other embodiments, treating a subject afflicted with PPMS comprises preventing further progression as determined by 12 week Confirmed Disease Progression (CDP) assessed by EDSS, compared to baseline. In yet other embodiments, treating a subject afflicted with PPMS comprises preventing further progression as determined by the time needed to complete a timed 25-foot walk (T25FW) test, compared to baseline. In further embodiments, treating a subject afflicted with PPMS comprises preventing further progression as determined by the time needed to complete a 9-Hole Peg Test (9-HPT), compared to baseline.

[0020] In one embodiment, the baseline is a period of 12 weeks or more prior to initiation of treatment by the depot formulation. In another embodiment, the baseline is a period of 1 year prior to initiation of treatment by the depot formulation.

[0021] In further embodiments, treating a subject afflicted with PPMS comprises achieving no evidence of disease progression (NEP).

[0022] In some embodiments, treating a subject afflicted with PPMS comprises decreasing (i) the number of new or enlarging T2 lesions; (ii) the volume of T2 lesions; (iii) the number of new or enlarging T1 lesions; (iv) the volume of T1 lesions; (v) the number or volume of Gadolinium (Gd) lesions; or (vi) any combination of (i) to (v). Each possibility represents a separate embodiment of the invention.

[0023] In various embodiments, treating a subject afflicted with PPMS comprises alleviating at least one symptom of PPMS. In particular embodiments, the symptom is selected from the group consisting of impaired coordination, impaired walking capability, impaired balance, weakness of the leg, stiffness of the leg, impaired memory, impaired cognitive function, a difficulty to swallow, impaired vision, general fatigue, pain, impaired bladder function, impaired bowel function, and any combination thereof. Each possibility represents a separate embodiment of the invention.

[0024] In certain embodiments, the subject has been diagnosed with PPMS for at least 1 year prior to initiation of the regimen. In other embodiments, the subject has an EDSS score of about 2 to about 5 and a sustained increment of > 1 point in the EDSS score in the last year prior to initiation of the regimen. In yet other embodiments, the subject has an EDSS score of >5 and a sustained increment of > 0.5 point in the EDSS score in the last year prior to initiation of the regimen. In further embodiments, the subject has a documented history of, or the presence of an oligoclonal band (OCB) (IgG OCB positive (OCGB+)) and / or positive IgG index in the cerebrospinal fluid (CSF) prior to initiation of the regimen. In additional embodiments, the subject has no documented history of a relapse event prior to initiation of the regimen.

[0025] In some embodiments, the depot formulation comprises a pharmaceutically acceptable biodegradable carrier selected from the group consisting of poly(lactic-co- glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and any combination thereof. Each possibility represents a separate embodiment. In other embodiments, the depot formulation comprises PLGA. In yet other embodiments, the PLGA is a poly(D,L-lactide-co-glycolide) (50:50) copolymer.

[0026] In certain embodiments, the depot formulation is formed by a water-in-oil-in- water double emulsification. In one embodiment, the depot formulation comprises microparticles comprising dried droplets, wherein the droplets comprise an internal aqueous phase comprising the GA, a water immiscible polymeric phase comprising a biodegradable carrier, and an external aqueous phase. In another embodiment, the external aqueous phase comprises a surfactant selected from poly(vinyl alcohol) (PVA), polysorbate, polyethylene oxide-polypropylene oxide block copolymers and cellulose esters. Each possibility represents a separate embodiment of the invention.

[0027] In various embodiments, the depot formulation is in the form of a suspension comprising from about 20% to about 30% of microparticles suspended in a pharmaceutically acceptable diluent for injection. In one embodiment, the pharmaceutically acceptable diluent for injection is water for injection. In further embodiments, the weight ratio between the GA and the pharmaceutically acceptable biodegradable carrier is between 1 : 1 to 1 : 100, including each ratio therebetween. In additional embodiments, the weight ratio between the GA and the pharmaceutically acceptable biodegradable carrier is between 1 :5 to 1 :25, including each ratio therebetween. In certain embodiments, the weight ratio between the GA and the pharmaceutically acceptable biodegradable carrier is between 1:5 to 1 : 15, including each ratio therebetween. In specific embodiments, the weight ratio between the GA and the pharmaceutically acceptable biodegradable carrier is between 1 : 10 to 1 : 12, including each ratio therebetween.

[0028] In certain embodiments, a plurality of administrations of the depot formulation of the invention is provided to the subject afflicted with PPMS. In some embodiments, the administration is repeated at least once. In other embodiments, the administration is repeated at least twice. In yet other embodiments, the administration is consecutively repeated for at least 6 months. In additional embodiments, the administration is consecutively repeated for at least 1 year.

[0029] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

[0030] BRIEF DESCRIPTION OF THE FIGURES

[0031] Figure 1 depicts a schematic representation of the phase lib study design.

[0032] Figure 2 depicts the EDSS score by visit. ■ - 40 mg GA depot; • - 25 mg GA depot.

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention provides long-acting depot formulations of a glatiramer salt, with significant therapeutic efficacy in PPMS patients, and reduced side effects resulting from infrequent administrations and a lower dose of the active ingredient. The invention is based on the surprising finding that glatiramer acetate (GA), previously deemed ineffective in multiple clinical studies of PPMS patients, was shown to be effective in treating PPMS patients when formulated as a depot system. Surprisingly, administration at a regimen of 25 mg GA depot once every 4 weeks resulted in reduced adverse effects and similar or enhanced efficacy as compared to a 40 mg dose administered at the same frequency.

[0035] Thus, provided herein is the treatment of a subject afflicted with PPMS. According to the principles of the present invention, the phrase “subject afflicted with PPMS” refers to a subject diagnosed as suffering from PPMS, i.e., in a progressive phase of MS as the primary manifestation of the disease.

[0036] An exemplary patient population to which treatment is beneficial includes subjects that were diagnosed with PPMS for at least 1 year prior to initiation of the regimen disclosed herein.

[0037] Another exemplary patient population to which treatment is beneficial includes subjects that are characterized by an EDSS score of about 2 to about 5, for example 2.0,

[0038] 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0,

[0039] 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5.0 and a sustained increment of> 1 point in the EDSS score in the last year prior to initiation of the regimen disclosed herein. Each possibility represents a separate embodiment.

[0040] An additional exemplary patient population to which treatment is beneficial includes subjects that are characterized by an EDSS score of >5, for example 5.1, 5.2,

[0041] 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2,

[0042] 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0 or more and a sustained increment of > 0.5 point in the EDSS score in the last year prior to initiation of the regimen disclosed herein. Each possibility represents a separate embodiment.

[0043] Further exemplary patient population to which treatment is beneficial includes subjects that had a documented history of, or the presence of an oligocl onal band (OCB) (IgG OCB positive (OCGB+)) and / or positive IgG index in the cerebrospinal fluid (CSF) prior to initiation of the regimen disclosed herein. In some embodiments, the patient had a documented history of, or the presence of more than 1 oligoclonal band (OCB) (IgG OCB positive (OCGB+)) and / or positive IgG index in the cerebrospinal fluid (CSF) prior to initiation of the regimen disclosed herein.

[0044] Other exemplary patient population to which treatment is beneficial includes subjects that are characterized by at least 1 gadolinium-enhancing lesion on MRI and / or at least 1 gadolinium-enhancing lesion documented within a previous year on MRI.

[0045] Yet other exemplary patient population to which treatment is beneficial includes subjects that are characterized by having at least two separate areas of damage in the central nervous system (CNS) that have occurred at different points in time. In certain embodiments, the patient has a history of at least one year of disease progression, and at least two from the group consisting of (i) at least one area of damage in the CNS, (ii) at least two areas of damage of a similar type in the spinal cord, and (iii) oligoclonal band in the spinal fluid or an elevated IgG index. Each possibility represents a separate embodiment of the invention.

[0046] Additional exemplary patient population to which treatment is beneficial includes subjects that had no documented history of a relapse event prior to initiation of the regimen disclosed herein. In some embodiments, the patient has no history of remission events. In other embodiments, the patient has not received GA therapy prior to initiation of the regimen. In yet other embodiments, the patient has not received a treatment prior to initiation of the regimen.

[0047] In some aspects and embodiments, treating PPMS comprises reducing the rate of progression of PPMS or a PPMS-related symptom. Treatment also includes increasing the time to onset of Confirmed Disease Progression (CDP), for example increasing the time to onset of 12 week Confirmed Disease Progression (CDP) assessed by EDSS, compared to baseline. The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these. The EDSS measures disability status on a scale ranging from 0 to 10, with higher scores indicating more disability. In other aspects and embodiments, treating comprises maintaining a substantially constant EDSS score, for example, preventing further progression of the disease as determined by 12 week Confirmed Disease Progression (CDP) assessed by EDSS, compared to baseline.

[0048] In yet other aspects and embodiments, treating PPMS comprises decreasing whole brain volume change or cortical volume change, compared to baseline. The T25FW is a quantitative mobility and leg function performance test where the participant is timed while walking for 25 feet. In certain embodiments, treating PPMS comprises decreasing the time needed to complete a timed 25-foot walk (T25FW) test, compared to baseline. In exemplary aspects and embodiments, treating comprises preventing further progression as determined by the time needed to complete a timed 25-foot walk (T25FW) test, compared to baseline.

[0049] The 9-HPT is a quantitative test of upper extremity function that measures the time it takes to place 9 pegs into 9 holes and then remove the pegs. In certain aspects and embodiments, treating PPMS comprises decreasing the time needed to complete a 9-Hole Peg Test (9-HPT), compared to baseline. In further aspects and embodiments, treating comprises preventing further progression as determined by the time needed to complete a 9-Hole Peg Test (9-HPT), compared to baseline.

[0050] The term “baseline” as used herein refers to a period of time before initiation of treatment by the method of the present invention. In some aspects and embodiments, the term “baseline” as used herein further refers to PPMS patients that are untreated by the method of the present invention. In other aspects and embodiments, the term “baseline” as used herein further refers to PPMS patients that are untreated. In particular aspects and embodiments, the term “baseline” as used herein refers a period of 12 weeks or more before initiation of treatment by the method of the present invention. In other particular aspects and embodiments, the term “baseline” as used herein refers a period of 6 months before initiation of treatment by the method of the present invention. In yet other particular aspects and embodiments, the term “baseline” as used herein refers a period of 1 year before initiation of treatment by the method of the present invention.

[0051] Treatment, according to the principles of the present invention, may also include at least one of the following: decreasing the number of new or enlarging T2 lesions; decreasing the volume of T2 lesions; decreasing the number of new or enlarging T1 lesions; decreasing the volume of T1 lesions; and decreasing the number or volume of Gadolinium (Gd) lesions as determined by Magnetic Resonance Imaging. Each possibility represents a separate embodiment. In some aspects and embodiments, treatment of PPMS comprises decreasing the change in whole brain volume and / or neocortical volume from baseline as determined by Magnetic Resonance Imaging.

[0052] Within the scope of the present invention is the treatment manifested by the alleviation, amelioration, reduction or elimination of at least one symptom associated with PPMS. Symptoms associated with PPMS include, but are not limited to, impaired coordination, impaired walking capability, impaired balance, weakness of the leg, stiffness of the leg, impaired memory, impaired cognitive function, a difficulty to swallow, impaired vision, general fatigue, pain, impaired bladder function, impaired bowel function, and any combination thereof. Each possibility represents a separate embodiment of the invention.

[0053] According to the principles of the present invention, treatment comprises the administration of a depot formulation comprising 25 mg glatiramer or salt thereof, for example glatiramer acetate, every 2-6 weeks. As used herein, the term “depot formulation” refers to a composition which provides prolonged, sustained or extended release of the glatiramer or glatiramer salt to the general systemic circulation of a subject or to local sites of action in a subject. This term may further refer to a composition which provides prolonged, sustained or extended duration of action (pharmacokinetics) of the glatiramer or glatiramer salt in a subject.

[0054] The term “glatiramer acetate” as used herein refers to a compound formerly known as Copolymer 1 that is sold under the trade name Copaxone® and consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate in Copaxone® is 4,700-11,000 Daltons (FDA Copaxone® label) and the number of amino acids ranges between about 15 to about 100 amino acids. The term also refers to chemical derivatives and analogues of the compound. Typically, the compound is prepared and characterized as specified in any of U.S. Pat. Nos. 5,981,589; 6,054,430; 6,342,476; 6,362,161; 6,620,847; and 6,939,539, the contents of each of these references are hereby incorporated in their entirety. The copolymers can be made by any procedure available to one of skill in the art. For example, the copolymers can be made under condensation conditions using the desired molar ratios of amino acids in solution, or by solid phase synthetic procedures. Condensation conditions include the proper temperature, pH, and solvent conditions for condensing the carboxyl group of one amino acid with the amino group of another amino acid to form a peptide bond. Condensing agents, for example, dicyclohexylcarbodiimide, can be used to facilitate the formation of the peptide bond.

[0055] In some embodiments, the composition may comprise any other pharmaceutically acceptable salt of glatiramer including, but not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, sulfonate, xylenesulfonate, methanesulfonate, propanesulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, nitrate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, tocopheryl succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4- dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, P-hydroxybutyrate, glycollate, tartrate, mandelate and the like salts. Each possibility represents a separate embodiment of the invention.

[0056] The frequency of administration within the scope of the present invention includes, once every 2 to 6 weeks, for example once every 3 to 5 weeks, preferably once every 4 weeks. Each possibility represents a separate embodiment. Within the scope of the present invention are repeated administrations. As used herein, the term “repeated administrations” refers to a plurality of administrations, i.e., at least one administration beyond a single administration. Thus, an administration which is repeated once refers to two administrations, an administration which is repeated twice refers to three administrations, etc. For example, repeated administrations encompassed by the present invention include, but are not limited to, administrations during a period of at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months or more at the specified frequency. Each possibility represents a separate embodiment of the invention.

[0057] Typically, the depot formulation is parenterally administered. In certain embodiments, the depot formulation is administered by intramuscular, subcutaneous, percutaneous, intravenous, or inhalation administration. Each possibility represents a separate embodiment of the invention. Currently preferred is the intramuscular administration.

[0058] According to the principles of the present invention, the depot formulation comprises 25 mg of a glatiramer salt encapsulated in a pharmaceutically acceptable biodegradable carrier. Pharmaceutically acceptable biodegradable carriers include, but are not limited to, poly(lactic- -gly colic acid) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and any combination thereof. Each possibility represents a separate embodiment. Currently preferred is the use of poly(Lactide-co-Glycolide) (PLGA) copolymer. The PLGA encompassed by the present invention may have a monomer ratio of lactic acid to glycolic acid in the range of 100:0 to 0: 100, for example in the range of 100:0 to 10:90, and has an average molecular weight from about 1,000 to about 200,000 Daltons, including each value within the specified ranges. PLGA polymers are commercially available from multiple suppliers, for example Alkermes (Medisorb polymers), Absorbable Polymers International [formerly Birmingham Polymers (a Division of Durect)], Ashland, Purac and Boehringer Ingelheim.

[0059] Suitable PLGA copolymers within the scope of the present invention include, but are not limited to, those containing lactic and glycolic monomers at a molar ratio of from 50:50 to 85: 15, including all iterations of ratios within the specified range. In some embodiments, the molar ratio of lactic to glycolic monomers in the PLGA is 50:50. In other embodiments, the molar ratio of lactic to glycolic monomers in the PLGA is 75:25. In yet other embodiments, the molar ratio of lactic to glycolic monomers in the PLGA is 85: 15.

[0060] While a single PLGA polymer can be used in the composition of the present invention, it is contemplated that two or more PLGA polymers can be admixed and used in the depot composition of the invention. According to some aspects and embodiments, the PLGA is characterized by acid termini, namely, the end groups of the polymer comprise lactic acid and / or glycolic acid. According to other aspects and embodiments, the PLGA is characterized by ester termini, namely, the end groups of the polymer comprise lactic acid ester and / or glycolic acid ester. A combination of a PLGA having acid termini and a PLGA having ester termini is also encompassed by the present invention.

[0061] According to some embodiments, the ratio between the glatiramer or a pharmaceutically acceptable salt thereof and the PLGA carrier is about 1 : 1 to about 1 : 100, including each value within the specified range. Thus, in some embodiments, the ratio between the glatiramer or a pharmaceutically acceptable salt thereof and the PLGA carrier is about 1 : 1 to about 1 :75, including each value within the specified range. In other embodiments, the ratio between the glatiramer or a pharmaceutically acceptable salt thereof and the PLGA carrier is about 1 : 1 to about 1:50, including each value within the specified range. In yet other embodiments, the ratio between the glatiramer or a pharmaceutically acceptable salt thereof and the PLGA carrier is about 1 : 1 to about 1 :40, including each value within the specified range. An exemplary ratio between the glatiramer or a pharmaceutically acceptable salt thereof and the PLGA carrier is about 1 :5 to about 1 :25, including each value within the specified range. Another exemplary ratio between the glatiramer or a pharmaceutically acceptable salt thereof and the PLGA carrier is about 1 :5 to about 1 : 15, including each value within the specified range. A further exemplary ratio between the glatiramer or a pharmaceutically acceptable salt thereof and the PLGA carrier is about 1 : 10 to about 1 : 12, including each value within the specified range.

[0062] The depot compositions of the present invention may further comprise one or more pharmaceutically acceptable excipient(s) selected from, but not limited to, cosurfactants, solvents / co-solvents, water immiscible solvents, water, water miscible solvents, oily components, hydrophilic solvents, emulsifiers, preservatives, antioxidants, anti-foaming agents, stabilizers, buffering agents, pH adjusting agents, osmotic agents, channel forming agents, osmotic adjustment agents, or any other excipient known in the art. Each possibility represents a separate embodiment of the invention. Suitable co-surfactants include, but are not limited to, polyethylene glycols, polyoxyethylene- polyoxypropylene block copolymers known as “poloxamer”, polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid ester such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan monooleate (Tween), polyethylene glycol fatty acid ester such as polyoxyethylene monostearate, polyoxyethylene alkyl ether such as polyoxyethylene lauryl ether, polyoxyethylene castor oil and hardened castor oil such as polyoxyethylene hardened castor oil, and the like or mixtures thereof. Each possibility represents a separate embodiment of the invention.

[0063] Suitable sol vents / co- solvents include, but not limited to, alcohols, triacetin, dimethyl isosorbide, glycofurol, propylene carbonate, water, dimethyl acetamide, and the like or mixtures thereof. Each possibility represents a separate embodiment of the invention.

[0064] Suitable anti-foaming agents include, but are not limited to, silicon emulsions or sorbitan sesquioleate.

[0065] Suitable stabilizers to prevent or reduce the deterioration of the components in the compositions of the present invention include, but are not limited to, antioxidants such as glycine, a -tocopherol or ascorbate, BHA, BHT, and the like or mixtures thereof. Each possibility represents a separate embodiment of the invention.

[0066] Suitable tonicity modifiers include, but are not limited to, mannitol, sodium chloride, and glucose. Each possibility represents a separate embodiment of the invention.

[0067] Suitable buffering agents include, but are not limited to, acetates, phosphates, and citrates with suitable cations. Each possibility represents a separate embodiment of the invention.

[0068] The depot systems of the present invention encompass any forms known to a person of skill in the art. Suitable forms include, but are not limited to, biodegradable microspheres, implantable rods, implantable capsules, and implantable rings. Each possibility represents a separate embodiment of the invention. Further contemplated are prolonged release gel depot and erodible matrices. Each possibility represents a separate embodiment of the invention. Currently preferred is the form of a suspension comprising from about 20% to about 30% of microparticles suspended in a pharmaceutically acceptable diluent for injection, for example water for injection. The term “water for injection” or “WFI” as used herein generally means sterile, pure water that meets regulatory standards for e.g., particulates, dissolved solids, organics, inorganics, microbial and endotoxin contaminants. In certain embodiments, the depot formulation is administered in WFI or a buffer containing a suspending agent (e.g., carboxymethylcellulose, CMC), a buffering agent (e.g., citrate salts) and / or a tonicity agent (e.g., NaCl).

[0069] According to the principles of the present invention, the depot formulation can be prepared as is known in the art. In some aspects and embodiments, the depot formulation comprises microparticles prepared by a process known as the “double emulsification” process. Briefly, an aqueous phase comprising glatiramer or a pharmaceutically acceptable salt thereof optionally comprising a surfactant (e.g., polyvinyl alcohol - PVA, polysorbates, polyethylene oxide-polypropylene oxide block copolymers, cellulose esters and the like) and / or a tonicity modifier (e.g., sodium chloride) is prepared. The pH of the aqueous solution may be adjusted to a range of about 6 to about 9, or about 7 to about 9, including each value within the specified ranges. Adjustment of the pH can be performed using any acid or base, for example sodium hydroxide. The aqueous phase is then dispersed in a solution of a biodegradable polymer in a water-immiscible volatile organic solvent (e.g., methylene chloride, chloroform and the like) optionally comprising a surfactant (e.g., a fatty acid or derivative thereof such as hydrogenated lecithin). The thus obtained “water-in-oil” (w / o) emulsion is then dispersed in a continuous external aqueous phase optionally containing a surfactant (e.g., polyvinyl alcohol - PVA, polysorbates, polyethylene oxide-polypropylene oxide block copolymers, cellulose esters and the like) and optionally a tonicity modifier (e.g., sodium chloride) to form “water-in-oil-in-water (w / o / w) double emulsion” droplets. After evaporation of the organic solvent, the microparticles solidify and are collected by filtration or centrifugation. The terms “oil phase” and “water-immiscible phase” may be used interchangeably herein. The collected microparticles (MPs) are washed (e.g., with purified water, or a buffer solution such as a phosphate buffer solution) to eliminate most of the surfactant and free peptide and centrifuged again. The washed MPs are collected and dried (e.g., lyophilized) without additives or with the addition of a cryoprotectant (mannitol) to facilitate their subsequent reconstitution.

[0070] According to further embodiments, the particle size of the “water-in-oil-in- water (w / o / w) double emulsion” droplets can be controlled by various parameters including, but not limited to, the amount of applied force, the speed of mixing, surfactant type and concentration, etc. Following solidification, the microparticles are typically characterized by particle sizes in the range of from about 1 to about 100 pm, including each value within the specified range. For example, the microparticles typically have sizes ranging from about 3 to about 70 pm, from about 3 to about 60 pm, or from about 3 to about 50 pm, with each possibility representing a separate embodiment of the present invention.

[0071] Encompassed by the present invention is a combination therapy of glatiramer acetate or any other pharmaceutically acceptable salt of glatiramer with at least one other active agent. Active agents within the scope of the present invention include, but are not limited to interferons, e.g., pegylated or non-pegylated a-interferons, or P- interferons, e.g., interferon P-la or interferon P-lb, or r-interferons; immunosuppressants with optionally antiproliferative / antineoplastic activity, e.g., mitoxantrone, methotrexate, azathioprine, cyclophosphamide, or steroids, e.g., methylprednisolone, prednisone or dexamethasone, or steroid-secreting agents, e.g., ACTH; adenosine deaminase inhibitors, e.g., cladribine; IV immunoglobulin G (e.g., as disclosed in Neurology, 1998, May 50(5): 1273-81), monoclonal antibodies to various T-cell surface markers, e.g., natalizumab (ANTEGREN®) or alemtuzumab; TH2 promoting cytokines, e.g., IL-4, IL-10, or compounds which inhibit expression of TH1 promoting cytokines, e.g., phosphodiesterase inhibitors, e.g., pentoxifylline; antispasticity agents including baclofen, diazepam, piracetam, dantrolene, lamotrigine, rifluzole, tizanidine, clonidine, beta blockers, cyproheptadine, orphenadrine or cannabinoids; AMPA glutamate receptor antagonists, e.g., 2,3-dihydroxy-6-nitro-7- sulfamoylbenzo(f)quinoxaline, [l,2,3,4,-tetrahydro-7-morpholin-yl-2,3-dioxo-6- (trifluoromethyl)quinoxalin-i-yl]methylphosphonate, l-(4-aminophenyl)-4-methyl- 7,8- methylene-dioxy-5H-2,3-benzodiazepine, or (-)l-(4-aminophenyl)-4-methyl-7,8- methylene-dioxy-4,5-dihydro-3-methylcarbarnoyl-2,3-benzodiazepine; inhibitors of VCAM-1 expression or antagonists of its ligand, e.g., antagonists of the a4pi integrin VLA-4 and / or a-4-P-7 integrins; anti-macrophage migration inhibitory factor (Anti- MIF); cathepsin S inhibitors; and mTor inhibitors. Each possibility represents a separate embodiment of the invention. Currently preferred one other active agent is FTY720 (2- amino-2-[2-(4-octylphenyl)ethyl] propane-1, 3-diol; fmgolimod) belonging to the class of immuno-suppressants. Another possibility is to combine glatiramer acetate depot with treatment by ocrelizumab (Ocrevus™), a humanized anti-CD20 monoclonal antibody, which is the only therapy currently approved for treatment of PPMS.

[0072] The following examples are presented in order to more fully illustrate certain embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

[0073] EXAMPLES

[0074] Example 1: Preparation of GA depot according to embodiments of the present invention

[0075] Preparation Process:

[0076] (1) Internal water phase preparation: A solution containing sterile water for injection (WFI) and glatiramer acetate was prepared and filtered through a 0.22 pm membrane.

[0077] (2) Organic phase preparation: Organic phase composed of dichloromethane and poly(lactide-co-glycolide) was prepared in a reactor and filtered through a 0.22 pm membrane.

[0078] (3) External water phase preparation: Partially hydrolyzed polyvinyl alcohol (PVA) solution at a concentration of 2% w / w in sterile WFI was prepared in a reactor and filtered through a 0.22 pm membrane. A solution of NaCl in sterile WFI was prepared and filtered through a 0.22 pm membrane into the reactor containing the PVA.

[0079] (4) Water-in-oil (w / o) emulsion preparation: The internal water phase was added to the organic phase and processed using IKA Ultra-Turrax T50 homogenizer equipped with a rotor stator dispersion device at 7,200 RPM for 10 minutes (high shear mixing).

[0080] (5) Water-in-oil-in-water (w / o / w) emulsion preparation: The water-in-oil emulsion (w / o) prepared in step (4) was added to half of the external water phase during continuing mixing of the w / o emulsion. The w / o / w double emulsion was processed using IKA Ultra-Turrax UTS80 homogenizer with a rotor stator head at 2,900 RPM for 3 minutes following the transfer of the w / o emulsion into the external water phase. Then, an additional portion of 30 liters of the external water phase was added to the emulsion (quench).

[0081] (6) Solvent removal / evaporation: The w / o / w double emulsion formed in step (5) was mixed using the IKA UTS80 homogenizer at different speeds for 15-17 hours. Compressed air was bubbled at 0.5 Pa through the emulsion for 10-12 hours. Vacuum was applied for the portion of the process.

[0082] (7) Separation and washing: The suspension was centrifuged at 5,300 RPM for 10 minutes. The supernatant was discarded and the pellet (sediment microparticles) was resuspended in 550 g WFI and mixed using a magnetic stirrer for 3 minutes. The resuspended microparticles were centrifuged at 2,900 RPM for 10 minutes.

[0083] (8) Lyophilization: The washed microparticles were resuspended in about 750 g sterile WFI and were kept at -20°C until lyophilization. Lyophilization was carried out using sterile lyoguard trays as follows: Freeze at -40°C, 24 hours. Primary drying at 0.2 hPa, -5°C, 48 hours. Secondary drying at 0.2 hPa, 10°C, 48 hours. The resulting composition included GA and PLGA (50:50, molecular weight 7,000-17,000) in a 1 : 11.5 weight ratio. The dry powder was dispensed into single dose vials to result in units doses, each containing 25 mg of GA.

[0084] Example 2: Phase lib study

[0085] A prospective, multicenter, two arms, open label, phase lib study to assess the safety and efficacy of 25 mg or 40 mg Glatiramer Acetate (GA) Depot prepared as described in Example 1 and administered intramuscularly (IM) once every 28 days to subjects with PPMS was performed. The study design is schematically shown in Figure 1. Thirty (30) primary progressive MS (PPMS) patients at the ages of 26-65 with documented fast disease worsening in the year before screening were enrolled. At baseline, the mean age was 53 evenly distributed between females and males. The patients had a rate of > 1- point increase per year in the EDSS score for EDSS between 2-5 and a rate of > 0.5-point increase per year in the EDSS scores > 5. The mean EDSS score of the patients was 5.1 with a range of 2.0-6.5. The patients had a documented history or positive oligoclonal band (OCB) test at screening and no documented relapse events prior to screening.

[0086] Safety assessment included the analysis of adverse events, hematology and chemistry blood tests. Efficacy assessments included EDSS, Nine-Hole Peg Test (9HPT) and Timed 25-Foot Walk (T25FW) tests (whereas change was defined as 12- week confirmed > ±20%), as well as MRI analysis. The number of subjects at each visit by dose group (n) is shown in Table 1.

[0087] Table 1.

[0088] Overall, most adverse events (83.5%) were mild, with injection site reactions being the most common. No unexpected adverse events were reported. Three serious adverse events were reported in the 40 mg dose, one of which was possibly related to the study drug. A lower rate of adverse events and injection site reactions was observed with the GA depot 25 mg compared to the 40 mg dose.

[0089] EDSS scores remained stable with only one 12-week confirmed disability progression (CDP). Notably, 72.4% of patients showed no evidence of progression (NEP), defined by the absence of 12-week CDP (96.6%), 12-week T25FW progression (79.3%), and 12-week 9HPT progression (93.1%). MRI analysis indicated low MRI activity. Surprisingly, while 68.4% of the patients receiving the 40 mg dose showed NEP, 80% of the patients receiving the 25 mg dose showed no NEP (Figure 2).

[0090] These findings indicate that the GA depot formulation according to embodiments of the present invention is safe and provides an effective treatment of PPMS patients with a remarkable NEP, stable EDSS, and more stable T25FW and 9HPT. The 25 mg dose shows a favorable trend in efficacy with improved safety and tolerability.

[0091] Additional data on safety and efficacy were collected and analyzed after completion of three years of study. Three serious adverse events were reported, all in the 40 mg dose group, but only erythema nodosum which was recorded in one patient during the second year of the study, was found to be related to the drug. No systemic immediate post-injection reactions were recorded. The most common adverse events in the 40 mg group were injection site pain (50% of patients), asthenia (45% of patients), pyrexia (40% of patients), pain in extremity (20% of patients), injection site swelling (20% of patients), injection site mass (15% of patients), headache (15% of patients), and muscle spasticity (15% of patients). The most common adverse events in the 25 mg group were pyrexia (20% of patients), urinary tract infection (20% of patients), hypercholesterolemia (20% of patients), back pain (20% of patients), and intervertebral disc protrusion (20% of patients). In the 40 mg dose, there was an incidence of a mild injection site induration, as well as incidences of mild to severe injection site reactions including injection site mass, pain, swelling, warmth, and pustule. In contrast, in the 25 mg dose, a single incidence of a mild injection site pain was recorded.

[0092] Efficacy assessment determined that subjects with active PPMS prior to screening showed stable EDSS scores in both treatment groups with only one patient having a 12-week CDP in the 25 mg group. No 12 weeks confirmed progression in T25FW of >20% was detected in 73.7% of the 40 mg group vs. 90% of the 25 mg group. In addition, no 12 weeks confirmed progression in 9HPT of >20% was detected in 89.5% of the 40 mg group vs. 90% of the 25 mg group. No evidence of progression (NEP) was comparable between the 40 and 25 mg groups (68.4% and 70%, respectively). The percent of brain volume change from baseline was shown to correlate with the EDSS score data. Taken together, the data indicate that the 25 mg dose shows a clear trend of lower incidences and rates of adverse events and injection site reactions as compared to the 40 mg dose with no severe adverse effects detected. In addition, the therapeutic efficacy of the 25 mg dose was shown to be at least comparable, and in some parameters superior, to the efficacy of the 40 mg dose.

[0093] While the present invention has been particularly described, persons skilled in the art will appreciate that many variations and modifications can be made. Therefore, the invention is not to be construed as restricted to the particularly described embodiments, and the scope and concept of the invention will be more readily understood by reference to the claims, which follow.

Claims

CLAIMS1. A depot formulation comprising a 25 mg dose of glatiramer acetate (GA) for use in treating a subject afflicted with primary progressive multiple sclerosis (PPMS), wherein the formulation is adapted for a therapeutically effective regimen of a single intramuscular injection every 2 to 6 weeks.

2. The depot formulation for use of claim 1, wherein the depot formulation is adapted for a therapeutically effective regimen of a single intramuscular injection every3 to 5 weeks.

3. The depot formulation for use of claim 2, wherein the depot formulation is adapted for a therapeutically effective regimen of a single intramuscular injection every4 weeks.

4. The depot formulation for use of any one of claims 1 to 3, wherein the subject has been diagnosed with PPMS for at least 1 year prior to initiation of the regimen.

5. The depot formulation for use of any one of claims 1 to 4, wherein the subject has an EDSS score of about 2 to about 5 and a sustained increment of > 1 point in the EDSS score in the last year prior to initiation of the regimen.

6. The depot formulation for use of any one of claims 1 to 4, wherein the subject has an EDSS score of >5 and a sustained increment of > 0.5 point in the EDSS score in the last year prior to initiation of the regimen.

7. The depot formulation for use of any one of claims 1 to 6, wherein the subject has a documented history of, or the presence of an oligoclonal band (OCB) (IgG OCB positive (OCGB+)) and / or positive IgG index in the cerebrospinal fluid (CSF) prior to initiation of the regimen.

8. The depot formulation for use of any one of claims 1 to 7, wherein the subject has no documented history of a relapse event prior to initiation of the regimen.

9. The depot formulation for use of any one of claims 1 to 8, wherein treating a subject afflicted with PPMS comprises at least one of: reducing the rate of progressionof PPMS; increasing the time to onset of Confirmed Disease Progression (CDP); increasing the time to onset of 12 week Confirmed Disease Progression (CDP) assessed by EDSS, compared to baseline; decreasing whole brain volume change or cortical volume change, compared to baseline; decreasing the time needed to complete a timed 25-foot walk (T25FW) test, compared to baseline; and decreasing the time needed to complete a 9-Hole Peg Test (9-HPT), compared to baseline.

10. The depot formulation for use of any one of claims 1 to 8, wherein treating a subject afflicted with PPMS comprises at least one of: maintaining a substantially constant EDSS score; preventing further progression as determined by 12 week Confirmed Disease Progression (CDP) assessed by EDSS, compared to baseline; preventing further progression as determined by the time needed to complete a timed 25-foot walk (T25FW) test, compared to baseline; and preventing further progression as determined by the time needed to complete a 9-Hole Peg Test (9-HPT), compared to baseline.

11. The depot formulation for use of claim 9 or 10, wherein the baseline is a period of 12 weeks or more prior to initiation of treatment by the depot formulation.

12. The depot formulation for use of claim 11, wherein the baseline is a period of 1 year prior to initiation of treatment by the depot formulation.

13. The depot formulation for use of any one of claims 1 to 8, wherein treating a subject afflicted with PPMS comprises decreasing (i) the number of new or enlarging T2 lesions; (ii) the volume of T2 lesions; (iii) the number of new or enlarging T1 lesions; (iv) the volume of T1 lesions; (v) the number or volume of Gadolinium (Gd) lesions; or (vi) any combination of (i) to (v).

14. The depot formulation for use of any one of claims 1 to 8, wherein treating a subject afflicted with PPMS comprises alleviating at least one symptom of PPMS.

15. The depot formulation for use of claim 14, wherein the symptom is selected from the group consisting of impaired coordination, impaired walking capability, impaired balance, weakness of the leg, stiffness of the leg, impaired memory, impaired cognitive function, a difficulty to swallow, impaired vision, general fatigue, pain, impaired bladder function, impaired bowel function, and any combination thereof.

16. The depot formulation for use of any one of claims 1 to 15, wherein the depot formulation comprises a pharmaceutically acceptable biodegradable carrier selected from the group consisting of poly(lactic- -gly colic acid) (PLGA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and any combination thereof.

17. The depot formulation for use of claim 16, wherein the depot formulation comprises PLGA.

18. The depot formulation for use of claim 17, wherein the PLGA is a poly(D,L- lactide-co-glycolide) (50:50) copolymer.

19. The depot formulation for use of any one of claims 16 to 18, wherein the weight ratio between the GA and the pharmaceutically acceptable biodegradable carrier is between 1 : 1 to 1 : 100.

20. The depot formulation for use of claim 19, wherein the weight ratio between the GA and the pharmaceutically acceptable biodegradable carrier is between 1 :5 to 1 :25.

21. The depot formulation for use of claim 20, wherein the weight ratio between the GA and the pharmaceutically acceptable biodegradable carrier is between 1 :5 to 1 : 15.

22. The depot formulation for use of claim 21, wherein the weight ratio between the GA and the pharmaceutically acceptable biodegradable carrier is between 1 : 10 to 1 : 12.

23. The depot formulation for use of any one of claims 1 to 22, wherein the depot formulation is in the form of a suspension comprising from about 20% to about 30% of microparticles suspended in a pharmaceutically acceptable diluent for injection.

24. The depot formulation for use of claim 23, wherein the pharmaceutically acceptable diluent for injection is water for injection.

25. The depot formulation for use of any one of claims 1 to 24, wherein the depot formulation is formed by a water-in-oil-in-water double emulsification.

26. The depot formulation for use of any one of claims 1 to 25, wherein the depot formulation comprises microparticles comprising dried droplets, wherein the dropletscomprise an internal aqueous phase comprising the GA, a water immiscible polymeric phase comprising a biodegradable carrier, and an external aqueous phase.

27. The depot formulation for use of claim 26, wherein the external aqueous phase comprises a surfactant selected from poly(vinyl alcohol) (PVA), polysorbate, polyethylene oxide-polypropylene oxide block copolymers and cellulose esters.

28. A method of treating a subject afflicted with primary progressive multiple sclerosis (PPMS), the method comprising administering to the subject a therapeutically effective regimen of a single intramuscular injection of a depot formulation comprising a 25 mg dose of glatiramer acetate (GA) every 2 to 6 weeks.

29. Use of a depot formulation comprising a 25 mg dose of glatiramer acetate (GA) for the preparation of a medicament for treating a subject afflicted with primary progressive multiple sclerosis (PPMS), wherein the formulation is adapted for a therapeutically effective regimen of a single intramuscular injection every 2 to 6 weeks.

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