Glatiramer depot system for treating progressive multiple sclerosis

Abstract

The present invention provides methods for treating or ameliorating primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS), and associated symptoms, by administering or implanting a depot formulation comprising a glatiramer salt, such as glatiramer acetate (GA). [Selection diagram] None

Description

Technical Field

[0001] The present invention relates to depot formulations for long-term release of glatiramer acetate or other pharmaceutically acceptable salts of glatiramer for the treatment of primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), and other implantable systems.

Background Art

[0002] Copolymer-1, also known as glatiramer acetate (GA) and marketed under the trade name Copaxone®, contains the acetate salt of a random copolymer of four amino acids, namely L-glutamic acid, L-alanine, L-tyrosine and L-lysine. Glatiramer acetate is the acetate salt of a mixture of synthetic polypeptides, each of which consists essentially of the four naturally-derived amino acids L-glutamic acid, L-alanine, L-tyrosine and L-lysine with average molar fractions of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glatiramer acetate is from 5000 to dalton. Glatiramer acetate is sold in the United States as Copaxone® and is approved for reducing the relapse frequency in patients with relapsing-remitting multiple sclerosis (RRMS).

[0003] Copaxone® has been approved since 1996 for the treatment of relapsing-remitting multiple sclerosis (RRMS) at a dose of 20 mg administered by daily subcutaneous injection. Since 2014, Copaxone® has also been approved for administration at a dose of 40 mg by three injections per week administered at least 48 hours apart. Compared to the daily administration of the 20 mg dose of Copaxone®, the latter dose and regime reduce the number of annual injections by about 200 while maintaining the same efficacy.

[0004] Copaxone® treatment, administered daily and three times weekly, involves self-injection of the active substance. Common injection site problems include irritation, hypersensitivity, inflammation, pain, and even necrosis (in the case of interferon-1β treatment), as well as resulting patient compliance issues. Common side effects include injection site lumps (injection site reactions), pain, fever, and chills. These side effects are generally mild. Occasionally, reactions occur a few minutes after injection and include flushing, shortness of breath, anxiety, and rapid heartbeat. These side effects subside within 30 minutes. Over time, visible depressions at the injection site may occur due to local destruction of adipose tissue, known as adipose tissue atrophy. Therefore, alternative administration methods are preferable. According to the FDA prescription label, several serious side effects have been reported with glatiramer acetate, including serious side effects on the cardiovascular, digestive (including the liver), hematological and lymphatic, musculoskeletal, nervous, respiratory, special sensory (particularly the eyes), and genitourinary systems. Metabolic and nutritional disorders have also been reported, but the link between glatiramer acetate and these adverse effects has not been definitively established (FDA label for Copaxone®).

[0005] Parenteral routes, including intravenous (IV), intramuscular (IM), or subcutaneous (SC) injection, are the most common and effective forms of delivery for both small and large molecular weight drugs. However, the pain, discomfort, and inconvenience of needle sticks make this mode of drug delivery the least preferred by patients. Therefore, any drug delivery technique that can reduce at least the total number of injections is preferable. Reducing the frequency of administration of such drugs during implementation can be achieved by using injectable depot formulations that can release the drug in a slow but predictable manner, thereby improving compliance. For most drugs, depending on the dose, it may be possible to reduce the injection frequency from daily to once or twice a month or for longer periods (6 months). In addition to improving patient comfort, less frequent injections of drugs in the form of depot formulations have been shown to reduce undesirable events, such as immunogenicity, which is often associated with large molecular weight drugs.

[0006] Microparticles, implants, and gel formulations are the most common forms of biodegradable polymer devices used in administration to extend drug release within the body. Microparticles are suspended in an aqueous medium immediately before injection and can contain up to 40% solid material in the suspension. Implant / rod formulations are delivered to SC / IM tissue in a dry state using a special needle, without the need for an aqueous medium. This characteristic of rods / implants allows for a larger mass of formulation and delivered drug content. Furthermore, with rods / implants, the area within the implant is much smaller compared to microparticles, minimizing the problem of initial burst. In addition to biodegradable systems, there are non-biodegradable implants and infusion pumps that can be worn outside the body. Non-biodegradable implants require examination not only for implantation of the device into SC / IM tissue but also for removal of those devices after the drug release period.

[0007] Injectable compositions containing particulate formulations are particularly prone to problems. Particulate suspensions can contain as much as 40% solids, compared to 0.5% to 5% solids in other types of injectable suspensions. Furthermore, the microparticles used in injectable depot products range in size from approximately 250 μm (average 60 μm to 100 μm) to less than 5 μm, compared to the less than 5 μm particle size recommended for IM or SC administration. Higher concentrations of solids, as well as larger solid particle sizes, require larger needles (approximately 18 gauge to 21 gauge) for injection. Overall, despite the less frequent use of larger, more uncomfortable needles, patients still prefer considerably less frequent dosage forms to more frequent dosing regimens, such as daily or three-times-weekly drug administration with smaller needles.

[0008] Biodegradable polyesters, specifically poly(lactic acid) (PLA) and lactide-glycolide copolymers known as poly(lactide-co-glycolide) (PLGA), are the most common polymers used in biodegradable dosage forms. PLA is a hydrophobic molecule, while PLGA degrades faster than PLA due to its greater presence of hydrophilic glycoside groups. These biocompatible polymers undergo random non-enzymatic hydrocleavage of ester bonds to form lactate and glycolic acid, which are normal metabolic compounds in the body. Reabsorbable sutures, clips, and implants are among the earliest applications of these polymers. The Southern Research Institute developed the first synthetic reabsorbable suture (Dexon®) in 1970. The first patent describing the use of PLGA polymers in sustained-release dosage forms appeared in 1973 (U.S. Patent No. 3,773,919).

[0009] Today, PLGA polymers are commercially available from multiple suppliers. In addition to PLGA and PLA, natural cellulose polymers such as starch, starch derivatives, and dextran, as well as non-PLGA synthetic polymers, are also being explored as biodegradable polymers in such systems.

[0010] U.S. Patents 8,377,885 and 8,796,226, granted to several of the inventors, relate to long-acting pharmaceutical compositions comprising glatiramer acetate in depot form.

[0011] Ocrelizumab (OCREVUS®) is a humanized anti-CD20 monoclonal antibody that received Breakthrough Therapy Designation for PPMS from the Food and Drug Administration (FDA) in 2016. Ocrelizumab was approved by the FDA in 2017 for the treatment of multiple sclerosis and was the first FDA-approved drug for PPMS. Ocrelizumab is administered intravenously.

[0012] To date, long-acting formulations of glatiramer acetate are not commercially available for the treatment of MS patients. Ongoing clinical trials are being conducted to test the safety and / or efficacy of GA in depot form in relapsing-remitting MS. There is an unmet medical need in the treatment options for progressive MS. Preferably, such treatment may be administered in depot formulations to minimize the drug delivery process and the frequency of associated side effects. [Overview of the project]

[0013] The present invention provides a method for treating progressive multiple sclerosis (MS) and related symptoms, comprising administering or implanting a long-acting depot formulation of a pharmaceutically acceptable glatiramer salt, such as glatiramer acetate. According to various embodiments, the depot formulation is administered weekly, every few weeks, once a month, or every few months. According to further embodiments, the depot formulation provides the patient with a pharmaceutically acceptable salt of glatiramer, such as glatiramer acetate, in doses ranging from 10 mg to 100 mg.

[0014] This invention discloses for the first time that long-acting pharmaceutical compositions and depot formulations based on the principles of the present invention provide therapeutic efficacy in patients with primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS). Unexpectedly, it was further found that once every few weeks, a depot of 10 mg to 100 mg of glatiramer acetate based on the principles of the present invention was beneficial for patients with PPMS and SPMS.

[0015] In one embodiment, the present invention provides a method for treating or alleviating primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS), or at least one symptom of PPMS or SPMS in a patient diagnosed with PPMS or SPMS, using a depot formulation of GA. The method comprises administering to a patient a therapeutically effective regimen of a depot formulation comprising glatiramer acetate (GA) or another pharmaceutically acceptable salt of glatiramer, the regimen being sufficient to treat or alleviate PPMS, SPMS, or at least one symptom of PPMS or SPMS. According to a particular embodiment, the depot formulation comprises glatiramer acetate.

[0016] In certain embodiments, the patient is diagnosed with PPMS. In certain embodiments, the patient is diagnosed with SPMS.

[0017] In certain embodiments, treating PPMS or SPMS includes reducing the rate of progression of PPMS or SPMS. In certain embodiments, treating PPMS or SPMS includes increasing the time to confirmed disease progression (CDP). In certain embodiments, treating PPMS or SPMS includes increasing the time to confirmed disease progression (CDP) at 12 weeks as assessed by the EDSS, compared to baseline. In certain embodiments, treating PPMS or SPMS includes reducing whole brain volume variability or cortical volume variability, compared to baseline. In certain embodiments, treating PPMS or SPMS includes reducing the time required to complete the timed 25-foot walk (T25FW) test, compared to baseline. In certain embodiments, treating PPMS or SPMS includes reducing the time required to complete the 9-Hole Peg Test (9-HPT), compared to baseline.

[0018] In certain embodiments, treating PPMS or SPMS includes reducing (i) the number of new or increasing T2 lesions; (ii) the volume of T2 lesions; (iii) the number of new or increasing 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 present invention. In certain embodiments, treating PPMS or SPMS includes preventing further progression of PPMS or SPMS compared to baseline.

[0019] In certain embodiments, the above symptoms are selected from the group consisting of impaired coordination, impaired walking ability, impaired balance, leg weakness, leg stiffness, memory impairment, cognitive impairment, dysphagia, visual impairment, general fatigue, pain, bladder dysfunction, bowel dysfunction, and any combination thereof. Each possibility represents a separate embodiment of the present invention.

[0020] In certain embodiments, the depot formulation is administered once every 1 to 15 weeks. In certain embodiments, the depot formulation is administered once every 2 to 6 weeks. According to several embodiments, the administration includes an injection of the depot formulation once every 2 to 6 weeks. In certain embodiments, the depot formulation is administered once every 4 weeks. According to several embodiments, the administration includes an intramuscular injection of the depot formulation once every 4 weeks.

[0021] In certain embodiments, the depot formulation is administered parenterally. In certain embodiments, the depot formulation is administered intramuscularly, subcutaneously, percutaneously, intravenously, or by inhalation. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the depot formulation is administered intramuscularly. In certain embodiments, the depot formulation is administered subcutaneously.

[0022] In certain embodiments, the depot formulation is administered at a concentration of 20 mg of GA per 1 mL of carrier. In certain embodiments, the carrier is water for injection (WFI). In certain embodiments, the depot formulation contains 20% to 30% solid. In certain embodiments, the depot formulation contains poly(lactide-co-glycolide) (PLGA) copolymer. In certain embodiments, the PLGA copolymer is poly(D,L-lactide-co-glycolide) (50:50) copolymer. In certain embodiments, the depot formulation contains 550 mg of PLGA copolymer per 40 mg of GA. In certain embodiments, the PLGA copolymer at least partially encapsulates the GA. In certain embodiments, the depot formulation contains a dose of 40 mg to 80 mg of GA. In certain embodiments, the depot formulation contains a dose of 40 mg of GA. In certain embodiments, the depot formulation contains a dose of 80 mg of GA.

[0023] In certain embodiments, less than 45% of the GA is released from the depot formulation within 14 days in PBS at 37°C with continuous stirring. In certain embodiments, more than 90% of the GA is released from the depot formulation within 28 days in PBS at 37°C with continuous stirring.

[0024] In certain embodiments, the patient has (i) been diagnosed with PPMS or SPMS for at least one year and has had a sustained increase of 1 point or more on the EDSS score or a 0.5 point increase on the EDSS score in the previous year; (ii) has an EDSS score ranging from 2 to 5.5; (iii) a confirmed history or presence of more than 1 oligoclonal band (OCB) (IgG OCB positive (OCGB+)) and / or a positive IgG index in cerebrospinal fluid (CSF); (iv) at least one gadolinium-enhancing lesion on MRI and / or at least one gadolinium-enhancing lesion confirmed on MRI in the previous year; or (v) any combination of (i) to (iv). Each possibility represents a separate embodiment of the present invention. In certain embodiments, the patient has damage to at least two separate areas of the central nervous system (CNS) that occurred at different points in time. In certain embodiments, the patient has a history of disease progression of at least one year and has at least two of the following: (i) at least one injury area in the CNS, (ii) at least two similar types of injury areas in the spinal cord, and (iii) oligoclonal bands or a high IgG index in the cerebrospinal fluid. In certain embodiments, the patient has no history of relapse events. In certain embodiments, the patient has no history of remission events. In certain embodiments, the patient has never received GA therapy prior to the initiation of the regimen of the present invention. In certain embodiments, the patient has received GA therapy prior to the initiation of the regimen of the present invention. In certain embodiments, the patient has received daily GA therapy prior to the initiation of the regimen of the present invention. In certain embodiments, the patient has received GA therapy three times a week prior to the initiation of the regimen of the present invention.

[0025] In certain embodiments, multiple doses of the depot formulation of the present invention are provided to a subject requiring it. In certain embodiments, the regimen is repeated at least twice. In certain embodiments, the regimen is repeated for at least six months. In certain embodiments, the regimen is repeated for at least one year.

[0026] In certain embodiments, the dosing frequency is reduced compared to daily dosing of 20 mg of GA or three times weekly dosing of 40 mg of GA. In certain embodiments, the dose of GA administered is reduced compared to daily dosing of 20 mg of GA or three times weekly dosing of 40 mg of GA. Each possibility represents a separate embodiment of the invention.

[0027] In another aspect, the present invention further provides a method of enhancing tolerance in patients suffering from primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS) to GA treatment, the method comprising reducing the dosing frequency of GA to a therapeutically effective regimen of a depot formulation of GA or another pharmaceutically acceptable salt of glatiramer so as to enhance tolerance to GA treatment in the patient.

[0028] In certain embodiments, enhancing tolerance to GA treatment includes reducing the injection frequency. In certain embodiments, increasing tolerance to GA treatment includes reducing the frequency of injection site reactions. In certain embodiments, enhancing tolerance to GA treatment includes reducing the total drug dose of GA administered over a period of time. In certain embodiments, enhancing tolerance to GA treatment includes improving patient compliance.

[0029] In another aspect, the present invention further provides a method of enhancing the convenience of GA treatment in patients suffering from primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS) by reducing the dosing frequency of GA. The method includes reducing the dosing frequency by providing a therapeutically effective regimen of a depot formulation of GA or another pharmaceutically acceptable salt of glatiramer, thereby enhancing the convenience of GA treatment for the patient.

[0030] In another aspect, the present invention further provides a method for improving adherence to GA treatment in patients with primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS), the method comprising reducing the frequency of GA administration by providing a therapeutically effective regimen of a depot formulation of GA or another pharmaceutically acceptable salt of glatiramer, thereby increasing adherence to GA treatment in patients.

[0031] Further embodiments and the full scope of applicability of the present invention will become apparent from the detailed description given below. However, since various variations and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description, the detailed description and specific examples should be understood to be provided for illustrative purposes only, while illustrating preferred embodiments of the invention. [Brief explanation of the drawing]

[0032] [Figure 1] This figure shows the mean clinical score results for the C57BL / 6 mouse group, compared to saline control, copaxone® (GA 2 mg, days 0-8), and GA depot (GA 4 mg, day 0). * For all treatment groups compared to the untreated control, a one-factor ANOVA was performed followed by a one-sided t-test assuming unequal variances, with P<0.05. N=20 / group, + / - standard error. [Figure 2] This figure shows the average body weight results for the C57BL / 6 mouse group under physiological saline control, copaxone® (GA 2 mg, day 0-8), and GA Depot (GA 4 mg, day 0). * For all treatment groups compared to the untreated control, a one-factor ANOVA was performed followed by a one-sided t-test assuming unequal variances, with P<0.05. N=20 / group, + / - standard error. [Modes for carrying out the invention]

[0033] The present invention provides a long-acting depot formulation of glatiramer acetate (GA) that exhibits remarkable therapeutic efficacy in patients with PPMS or SPMS and reduces side effects as a result of low-frequency GA administration.

[0034] This invention is based on the surprising finding that GA, which was previously considered ineffective in multiple clinical studies of PPMS patients, is actually effective in treating patients with PPMS and SPMS when formulated as a depot system and administered at lower doses than expected.

[0035] In one aspect, the present invention provides a method for treating or alleviating PPMS or SPMS, or at least one symptom of PPMS or SPMS, in a patient diagnosed with PPMS or SPMS, the method comprising the step of applying to the patient a therapeutically effective regimen of a depot formulation comprising glatiramer acetate (GA) or another pharmaceutically acceptable salt of glatiramer, the regimen being sufficient to treat or alleviate PPMS or SPMS, or at least one symptom of PPMS or SPMS.

[0036] According to the principles of the present invention, the phrase "patient diagnosed with PPMS" or the term "PPMS patient" as used herein in the same sense refers to a patient diagnosed with PPMS, i.e., a patient in the progressive stage of MS. According to the principles of the present invention, the phrase "patient diagnosed with SPMS" or the term "SPMS patient" as used herein in the same sense refers to a subject diagnosed with SPMS, i.e., a subject after the relapse-remission phase of MS has effectively ended, after the onset of the progressive stage, and in the progressive stage.

[0037] In certain embodiments, the patient is diagnosed with PPMS. In certain embodiments, the patient diagnosed with PPMS is in the advanced stage of PPMS. In certain embodiments, the patient is diagnosed with SPMS. In certain embodiments, the patient diagnosed with SPMS is in the advanced stage of SPMS.

[0038] As used herein, the term “therapeutably effective regimen” is intended to determine the frequency and amount of GA administration that achieve the goal of treating or alleviating PPMS or SPMS, or treating or alleviating the symptoms of PPMS or SPMS. As used herein, the term “depot formulation” refers to a composition that provides a long-term, sustained, or extended release of glatiramer salt to the general systemic circulation of the subject or to a local site of action in the subject. This term may further refer to a composition that provides a long-term, sustained, or extended duration of action (pharmacokinetics) of glatiramer salt in the subject. As used herein, the terms “to treat” and “treatment” refer to the prevention, suppression, or alleviation of one or more symptoms after the onset of PPMS or SPMS.

[0039] As used herein, the term “glutiramer acetate” refers to the compound previously known as Copolymer 1, marketed under the trade name Copaxone®, and comprises an acetate of a synthetic polypeptide containing four naturally occurring amino acids, namely L-glutamic acid, L-alanine, L-tyrosine, and L-lysine, with average mole fractions of 0.141, 0.427, 0.095, and 0.338, respectively. The average molecular weight of glutiramer acetate in Copaxone® ranges from 4700 daltons to 11000 daltons (FDA Copaxone® labeling), and the number of amino acids ranges from approximately 15 to approximately 100 amino acids. The above term also refers to chemical derivatives and analogues of the compound. Typically, the above compounds are prepared and characterized as expressly provided in any of U.S. Patent Nos. 5,981,589; 6,054,430; 6,342,476; 6,362,161; 6,620,847; and 6,939,539, and the contents of each of these references, in whole, constitute part of this specification.

[0040] Copolymers can be prepared by any procedure available to those skilled in the art. For example, copolymers can be prepared under condensation conditions using amino acids in a desired molar ratio in solution, or by solid-phase synthesis procedures. Condensation conditions include appropriate 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, such as dicyclohexylcarbodiimide, can be used to facilitate the formation of peptide bonds.

[0041] In some embodiments, the composition may include, but is not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobroms, hydroiodides, acetates, nitrates, propions, decanoates, capries, acrylates, formates, isobutyrates, caprinates, heptanoates, propioates, oxalates, malons, succinates, tocopheryl succinate, suberinates, sebacinates, fumarates, maleates, butin-1,4-dioate, hexin-1,6-dioate The glatiramer may contain any other pharmaceutically acceptable salts, including salts of benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfons, xylene sulfons, phenyl acetate, phenylpropionates, phenyl butyrates, citrates, lactates, β-hydroxybutyrates, glycolates, tartrates, methanesulfons, propanesulfons, naphthalene-2-sulfonates, p-toluenesulfons, mandelates, etc. Each possibility represents a separate embodiment of the present invention.

[0042] In certain embodiments, the symptom is impaired coordination. In certain embodiments, the symptom is impaired walking ability. In certain embodiments, the symptom is impaired balance. In certain embodiments, the symptom is leg weakness. In certain embodiments, the symptom is leg stiffness. In certain embodiments, the symptom is memory impairment. In certain embodiments, the symptom is cognitive impairment. In certain embodiments, the symptom is dysphagia. In certain embodiments, the symptom is visual impairment. In certain embodiments, the symptom is general fatigue. In certain embodiments, the symptom is pain. In certain embodiments, the symptom is bladder dysfunction. In certain embodiments, the symptom is bowel dysfunction. In certain embodiments, the symptom is a combination of PPMS or SPMS symptoms.

[0043] In certain embodiments, the depot formulation is administered once every 1 to 15 weeks. In certain embodiments, the depot formulation is administered once every 1 to 10 weeks. According to some embodiments, administration includes injection. According to some embodiments, administration includes injection every 2 to 6 weeks. According to some embodiments, administration includes administration every 2 to 6 weeks. In certain embodiments, the depot formulation is administered once every 2 weeks. In certain embodiments, the depot formulation is administered once every 3 weeks. In certain embodiments, the depot formulation is administered once every 4 weeks. In certain embodiments, the depot formulation is administered once every 5 weeks. In certain embodiments, the depot formulation is administered once every 6 weeks. In certain embodiments, the depot formulation is administered parenterally. In certain embodiments, the depot formulation is administered intramuscularly, subcutaneously, percutaneously, intravenously, or by inhalation. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the depot formulation is administered intramuscularly. In certain embodiments, the depot formulation is administered subcutaneously.

[0044] In certain embodiments, the depot formulation is administered at a concentration of 10 mg of GA per 1 mL of carrier. In certain embodiments, the depot formulation is administered at a concentration of 20 mg of GA per 1 mL of carrier. In certain embodiments, the depot formulation is administered at a concentration of 40 mg of GA per 1 mL of carrier. In certain embodiments, the carrier is WFI. As used herein, the terms “water for injection” or “WFI” generally mean sterile pure water that meets regulatory standards for, for example, particulate matter, dissolved solids, organic matter, inorganic matter, microorganisms and endotoxin contaminants. In certain embodiments, the depot formulation is administered in WFI, or in a buffer containing a suspension agent (e.g., carboxymethylcellulose, CMC), a buffering agent (e.g., citrate), and / or an isotonic agent (e.g., NaCl).

[0045] In certain embodiments, the depot formulation contains 10% to 40% solid. In certain embodiments, the depot formulation contains 20% to 30% solid. In certain embodiments, the depot formulation contains poly(lactide-co-glycolide) (PLGA) copolymer. In certain embodiments, the PLGA copolymer is poly(D,L-lactide-co-glycolide) (50:50) copolymer. In certain embodiments, the depot formulation contains 150 mg to 1500 mg of PLGA copolymer per 40 mg of GA. In certain embodiments, the depot formulation contains 550 mg of PLGA copolymer per 40 mg of GA. In certain embodiments, the PLGA copolymer at least partially encapsulates the GA. In certain embodiments, the PLGA copolymer encapsulates the GA.

[0046] In certain embodiments, the depot formulation contains at least 20 mg of GA or another pharmaceutically acceptable salt. In certain embodiments, the depot formulation contains 20 mg to 1000 mg of GA or another pharmaceutically acceptable salt. In certain embodiments, the depot formulation contains 20 mg to 750 mg of GA or another pharmaceutically acceptable salt. In certain embodiments, the depot formulation contains 40 mg to 80 mg of GA. In certain embodiments, the depot formulation contains 40 mg of GA. In certain embodiments, the depot formulation contains 50 mg of GA. In certain embodiments, the depot formulation contains 60 mg of GA. In certain embodiments, the depot formulation contains 70 mg of GA. In certain embodiments, the depot formulation contains 80 mg of GA.

[0047] In certain embodiments, less than 30% of the GA is released from the depot formulation in PBS at 37°C with continuous stirring within 7 days. In certain embodiments, more than 20% of the GA is released from the depot formulation in PBS at 37°C with continuous stirring within 7 days. In certain embodiments, less than 45% of the GA is released from the depot formulation in PBS at 37°C with continuous stirring within 14 days. In certain embodiments, more than 30% of the GA is released from the depot formulation in PBS at 37°C with continuous stirring within 14 days. In certain embodiments, less than 85% of the GA is released from the depot formulation in PBS at 37°C with continuous stirring within 21 days. In certain embodiments, more than 40% of the GA is released from the depot formulation in PBS at 37°C with continuous stirring within 21 days. In certain embodiments, more than 90% of the GA is released from the depot formulation in PBS at 37°C with continuous stirring within 28 days.

[0048] In certain embodiments, in PBS at 37°C under continuous stirring, (i) approximately 14% of the glatiramer is released from the depot formulation within 0 days, and / or (ii) approximately 15% of the glatiramer is released from the depot formulation within 1 day, and / or (iii) approximately 21% of the glatiramer is released from the depot formulation within 5 days, and / or (iv) approximately 25% of the glatiramer is released from the depot formulation within 8 days, and / or (v) approximately 34% of the glatiramer is released from the depot formulation within 13 days, and / or (vi) approximately 43% of the glatiramer is released from the depot formulation within 15 days, and / or (vii) approximately 80% of the glatiramer is released from the depot formulation within 22 days, and / or (viii) approximately 96% of the glatiramer is released from the depot formulation within 27 days, and / or (x) approximately 99% of the glatiramer is released from the depot formulation within 32 days. Each possibility and each combination of possibilities represents a separate embodiment of the present invention.

[0049] In certain embodiments, treating PPMS or SPMS includes reducing the rate of progression of PPMS-related or SPMS-related symptoms. In certain embodiments, treating PPMS or SPMS includes reducing the rate of progression of PPMS or SPMS. In certain embodiments, treating PPMS or SPMS includes increasing the time to confirmed disease progression (CDP) compared to baseline, 12 weeks later as assessed by the EDSS. The Kurtzke Expanded Disability Status Scale (EDSS) is a method for quantifying physical disability in multiple sclerosis. The EDSS quantifies physical disability across eight functional systems (FS), allowing neurologists to assign a functional system score (FSS) to each of these. The EDSS measures the state of physical disability on a scale ranging from 0 to 10, with higher scores indicating more severe physical disability. In certain embodiments, treating PPMS or SPMS includes reducing whole-brain volume variability or cortical volume variability compared to baseline. The Time-25 Walk (T25FW) is a quantitative motor skills and leg function performance test that measures the time it takes a participant to walk 25 feet. In certain embodiments, treating PPMS or SPMS includes reducing the time taken to complete the Time-25 Walk (T25FW) compared to baseline. The 9-Hole Peg Test (9-HPT) is a quantitative upper limb function test that measures the time taken to insert nine pegs into nine holes and then remove them. In certain embodiments, treating PPMS includes reducing the time taken to complete the 9-Hole Peg Test (9-HPT) compared to baseline. The terms “baseline” and “control” are used interchangeably and refer herein to the period before initiating treatment by the methods of the present invention. In certain embodiments, the term “baseline” as used herein further refers to a patient with PPMS or SPMS who has not been treated by the methods of the present invention.In certain embodiments, the term “baseline” as used herein refers to the one-year period prior to commencing use of the treatment according to the method of the present invention.

[0050] In certain embodiments, CDP is defined as one or more of the following criteria and is confirmed using one or more of the following assessments: a sustained increase in EDSS score from baseline of 1 point or more if the baseline EDSS is 5.5 or less, or 0.5 points or more if the baseline EDSS is greater than 5.5. In certain embodiments, CDP is defined as a sustained (12 weeks or more) increase in EDSS from baseline of 1.0 point or more if the baseline EDSS was between 2.0 and 5.5 points, or an increase in EDSS of 0.5 points or more if the baseline EDSS was greater than 5.5 points.

[0051] In certain embodiments, treating PPMS or SPMS includes reducing the number of new or growing T2 lesions. In certain embodiments, treating PPMS or SPMS includes reducing the volume of T2 lesions. In certain embodiments, treating PPMS or SPMS includes reducing the number of new or growing T1 lesions. In certain embodiments, treating PPMS or SPMS includes reducing the volume of T1 lesions. In certain embodiments, treating PPMS or SPMS includes reducing the number or volume of gadolinium (Gd) lesions. In certain embodiments, treating PPMS or SPMS includes preventing further progression of PPMS or SPMS compared to baseline.

[0052] In certain embodiments, the patient has been diagnosed with PPMS for at least one year and has experienced a sustained increase of 1 point or more in their EDSS score during the previous year. In certain embodiments, the patient has an EDSS score ranging from 2 to 5.5. In certain embodiments, the patient has a confirmed history or presence of more than one oligoclonal band (OCB) (IgG OBC-positive (OCGB+) and / or positive IgG index in cerebrospinal fluid (CSF). In certain embodiments, the patient has at least one gadolinium-enhancing lesion on MRI and / or at least one gadolinium-enhancing lesion confirmed on MRI within the previous year. In certain embodiments, the patient has at least two separate lesions in the central nervous system (CNS) that occurred at different time points. In certain embodiments, the patient has a history of disease progression of at least one year and at least two from the group consisting of (i) at least one lesion in the CNS, (ii) at least two similar types of lesions in the spinal cord, and (iii) oligoclonal bands or high IgG index in the CSF. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the patient has no history of relapse events. In certain embodiments, the patient has no history of remission events. In certain embodiments, the patient has never received GA therapy prior to the initiation of the regimen. In certain embodiments, the patient has received GA therapy prior to the initiation of the regimen.

[0053] In certain embodiments, the regimen is repeated. In certain embodiments, the regimen is repeated at least twice. In certain embodiments, the regimen is repeated continuously for at least six months. In certain embodiments, the regimen is repeated continuously for at least one year. In certain embodiments, the regimen is repeated continuously throughout the patient's lifetime.

[0054] In certain embodiments, the frequency of administration is reduced compared to a daily dose of 20 mg of GA or a three-times-weekly dose of 40 mg of GA. In certain embodiments, the dose of GA administered is reduced compared to a daily dose of 20 mg of GA or a three-times-weekly dose of 40 mg of GA. Each possibility represents a separate embodiment of the present invention. In some embodiments, the present invention provides a long-term release or sustained action of glatiramer in the subject compared to an immediate-release formulation of substantially similar amounts of glatiramer acetate.

[0055] In another aspect, the present invention further provides a method for improving the tolerability of GA treatment in patients with primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS), the method comprising reducing the frequency of GA administration from daily subcutaneous injections of 20 mg of GA or three subcutaneous injections of 40 mg of GA over a period of 7 days with at least one day between each injection, to a therapeutically effective regimen of GA or another pharmaceutically acceptable salt depot formulation of glatiramer, thereby improving the tolerability of GA treatment in patients.

[0056] In certain embodiments, improving the tolerability of GA treatment includes reducing the frequency of injections. In certain embodiments, improving the tolerability of GA treatment includes reducing the frequency of injection site reactions.

[0057] In another aspect, the present invention further provides a method to improve the convenience of GA treatment for patients with primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS), the method comprising improving the convenience of GA treatment for patients by reducing the frequency of GA administration to a therapeutically effective regimen of a depot formulation of GA or another pharmaceutically acceptable salt of glatiramer.

[0058] In another aspect, the present invention further provides a method for improving adherence to GA treatment in patients with primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS), the method comprising improving adherence to GA treatment in patients by reducing the frequency of GA administration to a therapeutically effective regimen of a depot formulation of GA or another pharmaceutically acceptable salt of glatiramer.

[0059] In another aspect, the present invention further provides a depot formulation comprising glatiramer acetate (GA) or another pharmaceutically acceptable salt of glatiramer for use in a method for treating or alleviating PPMS, SPMS, or at least one symptom of PPMS or SPMS in a patient diagnosed with PPMS or SPMS, the method comprising the step of administering the depot formulation to the patient.

[0060] In another aspect, the present invention further provides a depot formulation comprising glatiramer acetate (GA) or another pharmaceutically acceptable salt of glatiramer for use in a method of improving the tolerability of GA treatment in patients with primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS), the method comprising reducing the frequency of GA administration from daily subcutaneous injections of 20 mg dose of GA or three subcutaneous injections of 40 mg dose of GA over a period of 7 days with at least one day between each injection, to administration of a depot formulation.

[0061] In another aspect, the present invention further provides a depot formulation comprising glatiramer acetate (GA) or another pharmaceutically acceptable salt of glatiramer for use in a method to improve the convenience of GA treatment in patients with primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS), the method comprising reducing the frequency of administration of GA to a therapeutically effective regimen of the depot formulation.

[0062] In another aspect, the present invention further provides a depot formulation comprising glatiramer acetate (GA) or another pharmaceutically acceptable salt of glatiramer for use in a method of improving adherence to GA treatment in patients with primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS), the method comprising reducing the frequency of administration of GA to a therapeutically effective regimen of the depot formulation.

[0063] In certain embodiments, the dosage forms include, but are not limited to, biodegradable injectable depot systems such as PLGA-based injectable depot systems; non-PLGA-based injectable depot systems; and biodegradable injectable gels or dispersions. Each possibility represents a separate embodiment of the present invention. As used herein, the term “biodegradable” refers to a component that corrodes or degrades on its surface over time, at least partially due to contact with substances found in the surrounding tissue fluid, or by cellular action. In particular, biodegradable components are not limited to, but include lactic acid polymers such as polylactide, e.g., poly(D,L-lactide), i.e., PLA; glycolic acid polymers such as polyglycolide (PGA), e.g., Lactel® from Durect; poly(D,L-lactide-co-glycolide), i.e., PLGA (Resomer® RG-504, Resomer® RG-502, Resomer® RG-504H, Resomer® RG-502H, Resomer® RG-504S, Resomer® RG-502S from Boehringer, and Lactel® from Durect); poly(e Polycaprolactones such as -caprolactone, i.e., PCL (Lactel® manufactured by Durect); polyanhydride; poly(sebacic acid) SA; poly(ricinoleic acid) RA; poly(fumaric acid), FA; poly(fatty acid dimer), FAD; poly(terephthalic acid), TA; poly(isophthalic acid), IPA; poly(p-{carboxyphenoxy}methane), CPM; poly(p-{carboxyphenoxy}propane), CPP; poly(p-{carboxyphenoxy}hexane) sCPH; polyamines, polyurethanes, polyesteramides, polyoltoesters {CHDM: cis / trans-cyclohexyl dimethanol, HD: 1,6-hexanediol} DETOU: (3,9-diethylidene-2,4,8,10-tetraoxaspirowndecane); polydioxanone; polyhydroxybutyrate; polyalkylene oxalate; polyamide; polyesteramide; polyurethane; polyacetal; polyketal; polycarbonate; polyorthocarbonate; polysiloxane; polyphosphazene; succinate; hyaluronic acid;These polymers include poly(malic acid); poly(amino acids); hydroxyvalerates; polyalkylene succinates; polyvinylpyrrolidone; polystyrene; synthetic cellulose esters; polyacrylic acid; polybutyric acid; triblock copolymers (PLGA-PEG-PLGA), triblock copolymers (PEG-PLGA-PEG), poly(N-isopropylacrylamide) (PNIPAAm), poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers (PEO-PPO-PEO), polyvaleric acid; polyethylene glycol; polyhydroxyalkylcellulose; chitin; chitosan; polyorthoesters and copolymers, terpolymers; lipids such as cholesterol and lecithin; poly(glutamic acid-co-ethylglutamate), etc., or mixtures thereof.

[0064] In some embodiments, the compositions of the present invention include, but are not limited to, biodegradable polymers selected from PLGA, PLA, PGA, polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyalkene anhydrides, gelatin, collagen, oxidized cellulose, polyphosphazene, and the like. Each possibility represents a separate embodiment.

[0065] In certain embodiments, the biodegradable polymer is a lactic acid polymer, more preferably polylactide, or poly(D,L-lactide-co-glycolide), i.e., PLGA. The biodegradable polymer is present in an amount of about 10% by weight to about 98% by weight of the composition. The lactic acid polymer has a monomer ratio of lactic acid to glycolic acid in the range of 100:0 to about 0:100, preferably 100:0 to about 10:90, and has an average molecular weight of about 1,000 to 2,000,000 daltons. However, it is understood that the amount of biodegradable polymer is determined by parameters such as the duration of use.

[0066] The compositions and formulations of the present invention may further comprise one or more pharmaceutically acceptable excipients selected from, but not limited to, auxiliary surfactants, solvents / cosolvents, water-immiscible solvents, water, water-miscible solvents, oily components, hydrophilic solvents, emulsifiers, preservatives, antioxidants, defoamers, stabilizers, buffers, pH adjusters, penetrants, channel-forming agents, osmotic pressure regulators, or any other excipients known in the art. Suitable auxiliary surfactants include, but are not limited to, polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymer known as "poloxamer," polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate, sorbitan fatty acid esters such as sorbitan monostearate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate (Tween), polyethylene glycol fatty acid esters such as polyoxyethylene monostearate, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene castor oil, and hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil, or mixtures thereof. Each possibility represents a separate embodiment of the present invention. Suitable solvents / cosolvents include, but are not limited to, alcohols, triacetin, dimethyl isosorbide, glycoflore, propylene carbonate, water, dimethylacetamide, or mixtures thereof. Each possibility represents a separate embodiment of the present invention. Suitable defoaming agents include, but are not limited to, silicone emulsion or sorbitan sesquioleate. Suitable stabilizers for preventing or reducing the degradation of components in the composition of the present invention include, but are not limited to, antioxidants such as glycine, α-tocopherol or ascorbate, BHA, BHT, or mixtures thereof. Each possibility represents a separate embodiment of the present invention. Suitable osmotic regulators include, but are not limited to, mannitol, sodium chloride, and glucose. Each possibility represents a separate embodiment of the present invention. Suitable buffering agents include, but are not limited to, acetates, phosphates, and citrates with suitable cations.Each possibility represents a separate embodiment of the present invention.

[0067] The particle size of the "water in oil (w / o / w) double emulsion" can be determined by various parameters, including, but not limited to, the amount of force applied in this process, the mixing rate, the type and concentration of the surfactant, etc. A suitable particle size is in the range of approximately 1 to 100 μm.

[0068] The depot systems of the present invention encompass any form known to those skilled in the art. Preferred forms, but not limited to, include biodegradable or non-biodegradable microspheres, embedded rods, embedded capsules, and embedded rings. Each possibility represents a separate embodiment of the present invention. Furthermore, long-term release gel depots and edible matrices are conceived. Each possibility represents a separate embodiment of the present invention. A preferred embedded system is described, for example, in U.S. Patent Application Publication No. 2008 / 0063687, the entirety of which forms part of this specification. Embedded rods can be manufactured using a suitable microextruder, as is known in the art.

[0069] In some embodiments, the depot formulations of the present invention include, but are not limited to, an aqueous suspension, oil phase, or wax phase of glatiramer acetate; a poorly soluble polymer electrolyte complex of glatiramer acetate; an "in-situ" gel-forming matrix based on a combination of glatiramer acetate and a water-miscible solvent; and biodegradable polymer microparticles incorporating glatiramer acetate. Each possibility represents a separate embodiment of the present invention. In particular, the compositions of the present invention are in the form of microparticles for injection, where glatiramer acetate is captured on a biodegradable or non-biodegradable carrier. The microparticle compositions of the present invention may also include a water-in-oil-in-water double emulsion. Microparticle compositions comprising an inner aqueous phase containing glatiramer or any pharmaceutically acceptable salt thereof, an oil phase or water-immiscible phase containing a biodegradable or non-biodegradable polymer, and an outer aqueous phase are included in the scope of the present invention. The outer aqueous phase may further include a surfactant, preferably polyvinyl alcohol (PVA), polysorbate, polyethylene oxide-polypropylene oxide block copolymer, or cellulose ester. The terms "oil phase" and "water-immiscible phase" may be used interchangeably in this specification.

[0070] According to some embodiments, glatiramer acetate comprises acetate salts of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine in molar ratios of about 0.14 glutamic acid, about 0.43 alanine, about 0.10 tyrosine, and about 0.33 lysine. According to other embodiments, glatiramer acetate or other pharmaceutically acceptable salts of glatiramer contain about 15 to about 100 amino acids.

[0071] In certain embodiments, the depot formulation is self-administered intramuscularly by the patient. In certain embodiments, the depot formulation is injected into the deltoid muscle.

[0072] The present invention encompasses combination therapy of glatiramer acetate or any other pharmaceutically acceptable salt of glatiramer with at least one other active substance. Active substances included in the scope of the present invention include, but are not limited to, interferons, e.g., PEGylated or non-PEGylated α-interferon, or β-interferon, e.g., interferon β-la or interferon β-1b, or τ-interferon; optionally immunosuppressants having antiproliferative / antitum activity, e.g., mitoxantrone, methotrexate, azathioprine, cyclophosphamide, or steroids, e.g., methylprednisolone, prednisone, or dexamethasone, or steroid secretants, e.g., ACTH; adenosine deaminase inhibitors, e.g., cladribine; and IV immunoglobulin G against various T cell surface markers (e.g., Neurology, 1998, May Monoclonal antibodies (disclosed in 50(5):1273-81), e.g., natalizumab (ANTEGREN®) or alemtuzumab; compounds that inhibit the expression of TH2-promoting cytokines, e.g., IL-4, IL-10, or TH1-promoting cytokines, e.g., phosphodiesterase inhibitors, e.g., pentoxyferin; antispasmodics including baclofen, diazepam, piracetam, dantrolene, lamotrigine, rifluzole, tizanidine, clonidine, beta-blockers, cyproheptadine, orphenadrine, or cannabinoids. Agents; AMPA glutamate receptor antagonists, e.g., 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline, [1,2,3,4-tetrahydro-7-morpholin-yl-2,3-dioxo-6-(trifluoromethyl)quinoxaline-i-yl]methylphosphonate, 1-(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-methylcarbanoyl-2,3-benzodiazepine;Examples include inhibitors of VCAM-1 expression or antagonists of its ligands, e.g., antagonists of α4β1 integrin VLA-4 and / or α-4-β-7 integrins, e.g., natalizumab (ANTEGREN®); anti-macrophage migration inhibitory factor (anti-MIF); xii) cathepsin S inhibitors; xiii) mTor inhibitors. Each possibility represents a separate embodiment of the present invention. One other currently preferred activator is FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl)propane-1,3-diol; fingolimod), which belongs to the class of immunosuppressants. Another possibility is the combination of treatment with ocrelizumab (OCREVUS®), a humanized anti-CD20 monoclonal antibody, with glatiramer acetate, which is currently the only approved treatment for PPMS.

[0073] In more specific embodiments, the sustained-release depot formulation contains a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, and the formulation is a sustained-release depot form that releases a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer over a period of about 1 week to about 6 months. In certain embodiments, the sustained-release depot formulation contains a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer in a depot form suitable for implantation at a medically acceptable site in a subject requiring it. In certain embodiments, the glatiramer contains L-alanine, L-glutamic acid, L-lysine, and L-tyrosine in a molar ratio of about 0.14 glutamic acid, about 0.43 alanine, about 0.10 tyrosine, and about 0.33 lysine. In certain embodiments, the glatiramer contains about 15 to about 100 amino acids. In certain embodiments, the sustained-release depot formulation further comprises a pharmaceutically acceptable biodegradable or non-biodegradable carrier. In certain embodiments, the carrier is selected from poly(D,L-lactide-co-glycolide)(PLGA), poly(D,L-lactide)(PLA), polyglycolide(PGA), polycaprolactone, polyhydroxybutyrate, polyorthoester, polyalkane anhydride, gelatin, collagen, oxidized cellulose, and polyphosphazene. In certain embodiments, the sustained-release depot formulation is in the form of microparticles produced by a water-in-oil-in-water double emulsion process. In certain embodiments, the sustained-release depot formulation comprises an inner aqueous phase containing a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer, a water-immiscible polymer phase containing a biodegradable or non-biodegradable polymer, and an outer aqueous phase. In certain embodiments, the water-immiscible polymer phase contains a biodegradable polymer selected from poly(D,L-lactide)(PLA) and poly(D,L-lactide-co-glycolide)(PLGA). In certain embodiments, the external aqueous phase comprises a surfactant selected from (form) polyvinyl alcohol (PVA), polysorbate, polyethylene oxide-polypropylene oxide block copolymer, and cellulose ester.In certain embodiments, the sustained-release depot formulation may be in the form of biodegradable microspheres, non-biodegradable microspheres, implants of any preferred geometric shape, implantable rods, implantable capsules, implantable rings, or long-release gels or edible matrices. In certain embodiments, the sustained-release depot formulation may provide therapeutic efficacy equal to or better than commercially available daily or three-times-weekly glatiramer acetate injectable formulations with reduced incidence and / or severity of side effects at the local and / or systemic levels. In certain embodiments, the sustained-release depot formulation may provide a long-release or sustained action of glatiramer in the subject compared to a substantially same dose of an immediate-release formulation of glatiramer acetate.

[0074] In certain embodiments, the sustained-release depot formulation further comprises at least one additional drug. In certain embodiments, the at least one additional drug is an immunosuppressant. In certain embodiments, the at least one additional drug is fingolimod. In certain embodiments, the sustained-release depot formulation comprises a pharmaceutically acceptable salt of glatiramer in a dose ranging from about 20 to about 750 mg. In certain embodiments, pharmaceutically acceptable salts of glatiramer include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobroms, hydroiodides, acetates, nitrates, propions, decanoates, capries, acrylates, formates, isobutyrates, caprinates, heptanes, propioates, oxalates, malons, succinates, tocopheryl succinate, suberates, sebacinates, fumarates, maleates, butin-1,4-dioate, The group consists of hexyn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenyl acetate, phenylpropionate, phenyl butyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, and mandelate. Each possibility represents a separate embodiment of the present invention. In a particular embodiment, the therapeutically acceptable amount of the pharmaceutically acceptable salt of the above glatiramer is about 1 mg / day to about 500 mg / day, or about 20 mg / day to about 200 mg / day.

[0075] The following embodiments are provided to more fully illustrate specific embodiments of the present invention. However, the following embodiments should not be construed as limiting the broad scope of the present invention. Those skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the present invention.

[0076] Examples Example 1: In vitro preparation method for 40 mg of GA in PLGA depot Preparation process: (1) Preparation of the outer aqueous phase: A solution of partially hydrolyzed polyvinyl alcohol (PVA) at a concentration of 2 wt / wt% was prepared in a reactor in sterile WFI and filtered through a 0.22 μm membrane. (2) A solution of NaCl in sterile WFI was prepared and filtered through a 0.22 μm membrane into a reactor containing PVA. (3) Preparation of the organic phase: An organic phase consisting of dichloromethane and poly(lactide-co-glycolide) was prepared in a reactor and filtered through a 0.22 μm membrane. (4) Preparation of the inner aqueous phase: A solution containing sterile WFI and acetic acid glutillamer was prepared and filtered through a 0.22 μm membrane. (5) Preparation of the water-in-oil (w / o) emulsion: The inner aqueous phase was added to the above organic phase and processed for 10 minutes at 7200 RPM (high shear mixing) using an IKA Ultra-Turrax T50 homogenizer equipped with a rotor stator dispersion unit. (6) Preparation of water-in-oil (w / o / w) emulsion: The water-in-oil (w / o) emulsion prepared in step 5 was added to half of the external aqueous phase while the w / o emulsion was being continuously mixed. The w / o / w double emulsion was processed using an IKA Ultra-Turrax UTS80 homogenizer equipped with a rotor stator head at 2900 RPM for 3 minutes from the end of the w / o transfer to the external aqueous phase. Subsequently, an additional 30 liters of the external aqueous phase were added to the emulsion (quench). (7) Solvent removal / evaporation: The w / o / w double emulsion formed in step (6) was mixed using an IKA UTS80 homogenizer at various rates for 15 to 17 hours. Compressed air was passed through the emulsion at 0.5 Pa for 10 to 12 hours. Vacuum was applied to part of the process. (8) Separation and Washing: The suspension was centrifuged at 5300 RPM for 10 minutes. The supernatant was discarded, and the pellet (sedimentary microparticles) was resuspended in 550 g of WFI and mixed for 3 minutes using a magnetic stirrer. The resuspended microparticles were centrifuged at 2900 RPM for 10 minutes. (9) Lyophilization: The washed microparticles were resuspended in approximately 750 g of sterile WFI and maintained at -20°C until lyophilization. Lyophilization was performed using a sterile Lyoguard tray as follows: Freezing at -40°C for 24 hours.Pre-drying at 0.2 hPa and -5°C for 48 hours. Secondary drying at 0.2 hPa and 10°C for 48 hours. The resulting composition contains GA and PLGA (50:50, molecular weight 7000-17000) in a weight ratio of 1:11.5.

[0077] Example 2: GA40mgin in vitro release profile from PLGA depot. The release of incorporated glutillamer acetate was performed in a tightly sealed 20 ml glass container using an incubator at 37°C equipped with a multipoint magnetic stirrer. Phosphate-buffered saline (PBS) at pH 7.4 was used as the release medium. Table 1 summarizes the GA release profile from the PLGA depot. [Table 1]

[0078] Example 3: In vivo depot administration of GA 40 mg versus commercially available GA (copaxone®) material and method Animals: All animal studies were approved by the Israeli MOH Laboratory Animals Committee. Female C57BL / 6 mice aged 7 to 9 weeks were randomly assigned to either a control group or a treatment group with similar mean weights. Animals were given free access to food and water throughout the experiments.

[0079] Induction of progressive EAE: To induce primary progressive EAE (PP-EAE) (Sayed et al., The Journal of Immunology, 2011, Vol. 186, 3294-3298), which is most similar to progressive MS in humans, emulsions of MOG35-55 (GL Biochem co. Ltd., Shanghai, China) in modified complete Freund adjuvant (CFA) (Sigma-Aldrich, St. Louis, Missouri, USA) were prepared as follows: Heat-sterilized M. tuberculosis strain H37RA (Sigma) was added to CFA to a final concentration of 4 mg / mL. Subsequently, 2 mg / mL of MOG35-55 was emulsified with an equal volume of modified CFA. EAE was induced by subcutaneous (SC) injection of this emulsion into one site on the shaved back of mice, followed by intraperitoneal injection of Bordetella pertussis toxin (Sigma) in PBS on day 0 and 48 hours after MOG immunization. A 21G needle was used for injection in the mice. This model exhibited a steady inflammatory phase from day 9 to day 15, with clear demyelination and axonal damage. After this phase, inflammation is usually minimal.

[0080] Measurements: Body weight was measured every two days from day 0 to day 28. EAE was assessed once daily from day 0 to day 28 after immunization using the mouse clinical scoring system (Table 2). For analysis, deceased animals were given a clinical score of 5 and the body weight recorded at the last measurement before the animal's death. [Table 2]

[0081] The following calculations were derived from raw clinical score data: the mean maximum score is the average of the highest scores observed for each mouse in a specific group up to a specified date for analysis; the mean duration of illness and mean onset date were calculated as follows: mean duration of illness = sum of (analysis date - disease onset date for each mouse) / (number of mice per group); mean onset date = (sum of disease onset dates for each mouse) / (number of mice per group). The area under the curve (AUC) for the clinical score was calculated using Microsoft Excel and represents the disease burden.

[0082] Glatiramer acetate depot (GA depot): GA depot was suspended in sterile water for injection (WFI) and immediately administered by intramuscular (IM) injection at the specified dose. The dose of GA depot is given according to the amount of active ingredient (i.e., GA depot 4 mg contains 4 mg of GA).

[0083] GA-binding antibody analysis: Five animals were sacrificed from each treatment group on day 35 after disease induction. Blood samples were collected, serum was isolated and stored at -80°C (see Tables 3 and 5).

[0084] ELISA plates were prepared as follows: Flat-bottom ELISA plates (Nunc) were coated overnight at 4°C with 100 μl of 50 μg / ml GA in 0.17 M borate buffer (BB) pH 8.0. The wells were emptied and washed at room temperature with phosphate-buffered saline (PBS) containing 0.05% Tween 20. After washing, 1% BSA was applied at room temperature (RT) for 2 hours to block nonspecific binding sites. Subsequently, the wells were washed three times with the washing solution.

[0085] The ELISA test was performed as follows: 100 μl of serum sample was diluted 1:1000 and added to the wells at 4°C for 18 hours (serum dilution was performed using PBS containing 1% BSA and 0.05% Tween 20). The wells were then washed three times at room temperature with phosphate-buffered saline (PBS) containing 0.5% Tween 20. Subsequently, 100 μl of 1:50000 diluted alkaline phosphatase conjugate AffinityPure goat anti-mouse IgG+IgM(H+L) (Jackson Laboratories) was added to the wells and incubated at room temperature for 2 hours. The wells were washed three times again with washing solution, and the color reaction was induced by adding 100 μl of the substrate p-nitrophenyl phosphate (Jackson Laboratories) and incubated at room temperature for 40–60 minutes. The reaction was terminated with 30 μl of 3N NaOH. Absorbance was then recorded at 405 nm using a microELISA reader (Dynatech). Each assay plate contained a positive anti-GA formation sample and a control of normal mouse serum (N=5).

[0086] The results were expressed as a binding index (BI) according to the following formula: Binding index = mean optical density of the tested serum / mean optical density of the control serum. The mean value for normal mouse serum was 0.230 OD, and the cutoff value for the binding index was 2.0 ± 1.0. Therefore, values ​​greater than 3.0 were considered positive.

[0087] Experimental Design: The research experimental design is clearly shown in Table 3. [Table 3]

[0088] Statistical analysis: Data was analyzed using Microsoft Excel. Each dataset was analyzed using one-factor analysis of variance (ANOVA) followed by a one-sided Student's t-test.

[0089] GA Depot Dosage Conversion Figure 1 shows the mean clinical score results for the saline control group (black circles), the 2 mg copaxone® group (black squares), and the GA Depot 4 mg group (gray triangles), with each group representing the recommended human dose range of 0, 20, and 40 mg, respectively (using an allometric 1:10 scale, as estimated from previous studies). * For all treatment groups compared to the untreated control, a one-factor ANOVA was performed followed by a one-sided t-test assuming unequal variances, with P<0.05. N=20 / group, + / - standard error.

[0090] The mean clinical score AUC (area under the curve), mean day onset, and mean duration of illness were significantly reduced in the GA Depot and Copaxone® groups compared to the untreated control group (Table 4, p<0.05). No statistically significant differences were observed between GA Depot and Copaxone® in any calculation (Table 4). From days 11 to 19, the mean clinical score in the saline group was significantly higher than that of all other groups (Figure 1, p<0.05). On day 20, the mean clinical score in the saline group was significantly higher than that of the Copaxone® and GA Depot groups (Figure 1, P<0.05). Body weight in the GA Depot and Copaxone® treatment groups was significantly greater than that of the untreated control group from days 10 to 17 after immunization. On day 21, the body weight of the copaxone® group was significantly greater than that of the untreated control group (Figure 2, P<0.05). * P<0.05 was observed for all treatment groups compared to the untreated control. ** For copaxone® compared to an untreated control, a one-factor ANOVA was performed followed by a one-sided t-test assuming unequal variances, resulting in a p-value of < 0.05. N=20 / group, + / - standard error. [Table 4]

[0091] Immunological response in mice measured by antibodies against GA Serum was isolated from mice in the MOG-EAE study 35 days after disease induction. Mice were treated with either GA Depot (4 mg once) or Copaxone® (2 mg / day, days 0–8). Antibody (Ab) titers were evaluated using an ELISA assay. Results are expressed as binding index (BI). N=5. The data shown in Table 5 demonstrate that mice exposed to Copaxone® or GA Depot exhibited similar titers of all anti-GA antibodies, while control mice treated with saline did not possess such antibodies. Antibody titers were similar across all treatment groups, suggesting a similar immunological response. [Table 5]

[0092] The data presented, comparing the effect of a single dose of GA4 mg depot to a standard daily dose of GA2 mg, show similar efficacy between the two drug regimens. Specifically, GA depot demonstrated a clear and significant effect in delaying disease onset and alleviating symptoms, at least as effective as that observed in the copaxone® treatment group (see Figure 1).

[0093] Furthermore, this experiment demonstrates that intramuscular administration of GA depot induced a humoral response of anti-GA antibodies at a similar level to that of standard daily subcutaneous GA injections (see Table 5). Therefore, a similar humoral response to GA depot compared to standard GA injection may indicate a similarity in immunological responses to GA depot. This, therefore, may also suggest equivalent clinical immunological therapeutic effects, as seen in this EAE study, where the AUCs between copaxone® and GA depot do not differ in a statistically significant manner (see Table 4). Thus, the presence of anti-GA antibodies may serve as a biomarker for the therapeutic bioavailability of a drug when administered in a new formulation via a new route.

[0094] Overall, the data support that the efficacy of GA Depot at a 4 mg dose in MOG-induced EAEs is at least comparable to that of copaxone®, and that the immune response to both treatments is similar.

[0095] Example 4: Depot of 40 mg or 80 mg of GA in a person diagnosed with PPMS. Summary: A prospective, multicenter, single-arm, open-label, early-phase II study to evaluate the safety and efficacy of monthly long-acting intramuscular injections of 40 mg of glatiramer acetate (GA Depot) in subjects with primary progressive multiple sclerosis (PPMS).

[0096] Primary endpoints: Safety and tolerability: Assessment of adverse events (AEs); assessment of injection site reactions (ISRs).

[0097] Secondary endpoints: Efficacy: Time to confirmed disease progression (CDP) over 12 weeks as assessed by the EDSS; defined as an increase of at least one point from the baseline EDSS score that persisted for at least 12 weeks of subsequent outpatient visits. MRI assessment: Percentage change in whole brain volume; Percentage change in cortical volume.

[0098] Exploratory endpoints: Efficacy analysis: Change from baseline in time required to walk 25 feet (T25FW). Change from baseline in 9-HPT assessment. MRI assessment: New and increasing T2 lesions; T2 lesion volume; new and increasing T1 lesions; T1 lesion volume; number of gadolinium (Gd) lesions; gadolinium (Gd) lesion volume.

[0099] Procedure: Subjects will visit the facility every four weeks to receive intramuscular injections of GA Depot (40 mg) administered by a healthcare professional (HCP); they will be evaluated by the investigator at screening, baseline, one week after the second GA Depot injection, three months after the first injection, and every three months thereafter until the end of the treatment period. A follow-up (FU) visit to assess patient safety will be scheduled one month after End of Treatment (EoT).

[0100] Evaluation Criteria: LP:CSF Examination: Performed at the screening visit unless the subject had undergone a CSF examination prior to the screening visit. MRI Scan: Performed at screening, 24 weeks, and 52 weeks (EoT visit). Neurological evaluations, including EDSS, T25FW, and 9-HPT, were performed at screening, baseline, 3 months, and every 3 months thereafter until the end of treatment. Adverse Events (AEs): Monitored throughout the study period. Vital Signs: Blood pressure (BP) and heart rate were recorded at each visit. BP (systolic and diastolic) was measured twice at each visit (with several minutes between measurements). Physical Examination: A full physical examination was performed at screening, baseline, 1 week after the second depot treatment, 3 months after the first GA depot treatment, and every 3 months thereafter to ensure suitability according to inclusion and exclusion criteria. The final physical examination was performed at the FU visit. Laboratory Tests: Clinical tests related to chemistry, hematology, and urinalysis were performed at screening, baseline, 1 month, 3 months, 6 months, 9 months after the first treatment, and at EoT visits. Hematological tests included: hemoglobin, red blood cell count, MCV, hematocrit, MCH, white blood cell count, white blood cell percentage, and platelet count. Chemical tests included: creatinine, glucose, blood urea nitrogen (BUN), alkaline phosphatase, alanine aminotransferase (ALT / SGPT), aspartate aminotransferase (AST / SGOT), gamma-glutamyl transpeptidase (GGT), total bilirubin, protein, albumin, albumin / globulin ratio, sodium, potassium, chloride, calcium, uric acid, CPK, cholesterol, and triglycerides. Urinalysis - stick tests were performed in-house.

[0101] Each patient was compared to their individual baseline examinations performed at the time of the screening visit. Additional examinations may be performed at the investigator's discretion to ensure the subject's health status in the subject's best interests.

[0102] Antibody testing: Blood samples for detection of total glatiramer acetate IgG-binding antibody and neutralizing antibody against glatiramer acetate are collected at baseline, 1 month and 3 months after the first GA depot injection, and every 3 months thereafter. A 12-lead ECG is performed at screening. The ECG is recorded while the subject is at rest in a supine position. Six limb leads and six anterior chest leads (V1-V6) are used, as specified by Wilson, Einthoven (I, II, and III) and Goldberger (aVR, aVL, aVF). The investigator evaluates the parameters HR, RR, PQ, QRS, QT, and QTc. In addition, the occurrence of depolarization or repolarization disorders, arrhythmia disorders, or other abnormalities is evaluated and recorded. A chest X-ray is performed at screening if it has not been performed within 6 months prior to the screening visit.

[0103] Treatment site and patient instruction: The investigational injection will be administered and monitored at the site. Subjects will remain at the investigation site for 1 hour observation after the first GA depot and for 30 minutes after subsequent GA depots to ensure their health status.

[0104] Clinical trial treatment, dosage, and regimen for the investigational drug: All enrolled subjects will be treated with GA Depot (40 mg) IM at 4-week intervals over a total of 52 weeks of treatment.

[0105] Expected duration of subject participation, order, and overall clinical trial duration including follow-up: The trial duration for each subject is up to 14 months, consisting of a cleaning period and follow-up visits following 12 months of treatment, as follows: a screening period of up to 4 weeks (-4 weeks to 0 weeks), a 52-week open-label treatment period, an EoT visit at 52 weeks, and a follow-up visit 4 weeks after the EoT visit.

[0106] Subject Selection Criteria: Subjects must meet all of the following criteria before being enrolled in the study: Male or female subjects diagnosed with PPMS; diagnosis of PPMS is consistent with the MacDonald diagnostic criteria (2010 revision); age 18 to 60 years (inclusive); subjects diagnosed with PPMS for at least one year and with a sustained increase of 1 point or more on the EDSS score in the year prior to screening; EDSS ≥ 2 and ≤ 5.5 (pyramidal FS or cerebellar FS ≥ 2); more than 1 oligoclonal band (OCB) if quantitative testing is performed, or OCB+ if quantitative testing is not performed, and / or a confirmed history or presence of a positive IgG index in cerebrospinal fluid (CSF) at the time of screening; subjects with at least one gadolinium-enhancing lesion confirmed on baseline MRI and / or on previous MRI within 12 months prior to the screening visit; women of potential pregnancy must have a negative urine pregnancy test at the time of screening and must use appropriate contraception throughout the study; ability to provide written informed consent.

[0107] Subject Exclusion Criteria: A subject will be excluded from the study if any of the following criteria apply: RRMS, SPMS, or PRM; a history of confirmed recurrent events; any relevant medical, surgical, or psychiatric condition, clinical laboratory values, or concomitant medications that, in the investigator's opinion, would make the subject unsuitable for enrollment or likely prevent the subject from completing all aspects of the study; contraindications or inability to undergo a successful magnetic resonance imaging (MRI) scan; subjects diagnosed with any systemic autoimmune disease other than MS that may affect the CNS and involve MS-like lesions, such as sarcoidosis, Sjögren's syndrome, systemic lupus erythematosus (SLE), Lyme disease, or APLA syndrome; subjects with stable focal / organ autoimmune diseases such as psoriasis, cutaneous lupus erythematosus, or thyroiditis (Hashimoto's disease, Graves' disease). May be deemed eligible at the discretion of the PI; severe anemia (hemoglobin <10 g / dL); impaired renal function (serum creatinine >1.5 × ULN or creatinine clearance <30 ml / min); impaired hepatic function (transaminases >2 × ULN); pregnant or lactating women; treatment with any type of steroid in the month prior to the screening visit; a history of any anaphylactic reaction and / or severe allergic reaction after vaccination; known hypersensitivity to any component of the investigational drug, e.g., glatiramer acetate, polylactic acid-co-glycolic acid (PLGA), polyvinyl alcohol (PVA); a known or suspected history of drug or alcohol abuse; known to be positive for HIV, hepatitis, VDRL, or tuberculosis; any type of active malignancy. However, patients with a history of malignant disease, who have been treated for it, and who have been disease-free for at least the past seven years may be eligible at the discretion of the PI and the sponsor; prior treatment with B-cell targeted therapy (e.g., rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab) within six months prior to screening; prior treatment with cladribine within two years prior to the screening visit; prior treatment with azathioprine, mitoxantrone, or methotrexate within six months prior to the screening visit; prior treatment with lymphocyte trafficking regulators (e.g., natalizumab, fingolimod) within six months prior to the screening visit.Subjects must have a total lymphocyte count within the normal range; prior treatment with beta-interferon, intravenous immunoglobulin, or plasmapheresis within two months prior to the screening visit; prior treatment with any of the acetate glatiramer therapies within three months prior to the screening visit; uncontrolled diabetes; and participation in the investigational drug within 30 days prior to enrollment in the trial.

[0108] Formulation and Administration of Investigational Drug: GA Depot is a combination of sustained-release microspheres containing GA for injection and a diluent for parenteral use. The sustained-release microsphere formulation is a white to off-white fluid powder with an active ingredient content of 40 mg of GA per container. GA is microencapsulated in acid-terminated poly(D,L-lactide-co-glycoside) (50:50) at a concentration of 80 mg of GA per gram of microspheres plus a 10% excess to compensate for withdrawal losses. The diluent for parenteral use is sterile water for injection. The microspheres are suspended in the diluent before injection.

[0109] Investigational Treatment: IP: Long-acting glatiramer acetate (GA depot) formulation: 550 mg of lyophilized PLGA-encapsulated glatiramer acetate containing 40 mg of GA. Water for Injection (WFI): 10 ml ampoule. 1.6 ml of WFI was used to suspend one 40 mg GA depot vial to a final volume of 2 ml of injectable suspension. Route of Administration: Intramuscular. Unit Dose: 40 or 80 mg of GA depot. Dosage Schedule: Each subject received 13 doses of 40 or 80 mg of GA depot intramuscularly, once every 4 weeks, for a total of 52 weeks of treatment.

[0110] Details of efficacy / pharmacological parameters: The following clinical and efficacy parameters are evaluated: EDSS score; MRI assessment (whole brain volume, cortical brain volume, new and growing T2 lesions, T2 lesion volume, new and growing T1 lesions, T1 lesion volume, gadolinium (Gd)-lesion count, gadolinium (Gd)-lesion volume); time required to walk 25 feet (T25FW); and / or 9-HPT.

[0111] Although the present invention is described in detail individually, those skilled in the art will fully understand that many variations and modifications are possible. Therefore, the present invention is not to be construed as being limited to the embodiments described in detail individually, and the scope and concepts of the present invention will be readily understood by referring to the following claims.

Claims

1. 1. A method of treating or alleviating primary progressive multiple sclerosis (PPMS) or secondary progressive multiple sclerosis (SPMS) or symptoms thereof in a patient diagnosed with PPMS or SPMS, the method comprising administering to or implanting in the patient a sustained release depot formulation comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer.

2. The patient: (i) Diagnosed with PPMS for at least 1 year and with a persistent increase in EDSS score of 1 point or more in the last year; (ii) have an EDSS score of 2–5.5, including (≥2 pyramidal or cerebellar FS); (iii) have a confirmed history of, or the presence of, more than one oligoclonal band (OCB) if quantitative testing was performed, or OCB+ if quantitative testing was not performed, and / or a positive IgG index in the cerebrospinal fluid (CSF); (iv) at least one gadolinium-enhancing lesion on MRI and / or at least one gadolinium-enhancing lesion identified on MRI within the previous year, or (v) any combination of (i) to (iv); The method of claim 1.

3. 3. The method of claim 1 or claim 2, wherein the symptom is selected from the group consisting of impaired walking ability, leg weakness, leg stiffness, impaired balance, impaired coordination, impaired memory, impaired cognitive function, difficulty swallowing, impaired vision, general fatigue, pain, impaired bladder function, impaired bowel function, and any combination thereof.

4. Treating PPMS or SPMS can (i) increasing the patient's time to onset of confirmed disease progression (CDP) over 12 weeks as assessed by the Expanded Disability Status Scale (EDSS) compared to baseline or untreated controls; (ii) reducing the total brain volume change or cortical volume change in said patient compared to baseline or an untreated control; (iii) reducing the time required by said patient to complete the time to walk 25 feet (T25FW) test compared to baseline or untreated controls; (iv) reducing the time required by said patient to complete the 9-hole peg test compared to baseline or an untreated control; (v) reducing the number of new or enlarging T2 lesions in the brain of said patient compared to baseline or untreated controls; (vi) reducing the volume of T2 lesions in the brain of said patient compared to baseline or an untreated control; (vii) reducing the number of new or enlarging T1 lesions in the brain of said patient compared to baseline or an untreated control; (viii) reducing the volume of T1 lesions in the brain of said patient compared to baseline or an untreated control; (ix) reducing the number or volume of gadolinium (Gd) lesions in the brain of said patient compared to baseline or an untreated control; (x) reducing the rate of progression of PPMS or SPMS compared to baseline or untreated controls; (xi) preventing further progression of PPMS or SPMS compared to baseline or an untreated control; or (xii) Any combination of (i) to (xi) 4. The method of claim 1, comprising:

5. 5. The method of claim 4, wherein the patient has an EDSS score of less than 5.5 and the CDP is an increase in EDSS score of at least 1 point.

6. 5. The method of claim 4, wherein the patient has an EDSS score of 5.5 to 10 and the CDP is an increase in the EDSS score of at least 0.5 points.

7. 7. The method of any one of claims 4 to 6, wherein the baseline is a period of 12 weeks or more prior to treatment with the depot formulation.

8. 8. The method of claim 7, wherein the baseline is a one-year period prior to treatment with the depot formulation.

9. 9. The method of claim 1, wherein the depot formulation is administered systemically or implanted.

10. 10. The method of claim 9, wherein the depot formulation is administered or implanted intramuscularly, subcutaneously, transdermally, intravenously, or by inhalation.

11. 11. The method of claim 10, wherein the depot formulation is administered or implanted intramuscularly.

12. 12. The method of any one of claims 1 to 11, wherein the depot formulation comprises 10 mg to 100 mg of a pharmaceutically acceptable salt of glatiramer.

13. 13. The method of claim 12, wherein the depot formulation comprises a 40 mg to 80 mg dose of a pharmaceutically acceptable salt of glatiramer.

14. 14. The method of claim 13, wherein the depot formulation comprises a 40 mg dose of a pharmaceutically acceptable salt of glatiramer.

15. 14. The method of claim 13, wherein the depot formulation comprises an 80 mg dose of a pharmaceutically acceptable salt of glatiramer.

16. 16. The method of any one of claims 1 to 15, wherein the depot formulation is administered in a therapeutically effective regimen once every 1 to 15 weeks.

17. 17. The method of claim 16, wherein the depot formulation is administered once every four weeks.

18. 18. The method of claim 16 or claim 17, wherein the depot formulation is administered repeatedly for one year or more.

19. 19. The method of any one of claims 1 to 18, wherein the pharmaceutically acceptable salt of glatiramer is glatiramer acetate (GA).

20. 20. The method of any one of claims 1 to 19, wherein the depot formulation comprises 20% to 30% solids.

21. 21. The method of any one of claims 1 to 20, wherein the depot formulation comprises poly(lactide-co-glycolide) (PLGA) copolymer.

22. 22. The method of claim 21, wherein the PLGA copolymer is poly(D,L-lactide-co-glycolide) (50:50) copolymer.

23. 23. The method of claim 21 or claim 22, wherein the depot formulation comprises 550 mg of PLGA copolymer per 40 mg of the pharmaceutically acceptable salt of glatiramer.

24. 24. The method of any one of claims 21 to 23, wherein the PLGA copolymer at least partially encapsulates the pharmaceutically acceptable salt of glatiramer.

25. The depot formulation is prepared by mixing, in a closed container at 37° C., in phosphate buffered saline (PBS, pH 7.4), (i) releasing about 15% to about 30% of said glatiramer salt within 1 week; (ii) releasing about 30% to about 50% of the glatiramer salt within 2 weeks; (iii) releasing about 50% to about 90% of the glatiramer salt within 3 weeks; (iv) releasing about 90% to about 100% of the glatiramer salt within 4 weeks; or (v) any combination of (i) to (iv); 25. The method of any one of claims 1 to 24.

26. 26. The method of claim 25, wherein the depot formulation releases about 15% to about 30% of the glatiramer salt within 1 week, about 30% to about 50% of the glatiramer salt within 2 weeks, about 50% to about 90% of the glatiramer salt within 3 weeks, and about 90% to about 100% of the glatiramer salt within 4 weeks.

27. A method of increasing the tolerability or convenience of, or increasing adherence to, glatiramer treatment in a patient suffering from PPMS or SPMS and receiving an immediate-release or bolus glatiramer formulation, comprising reducing the frequency of glatiramer administration by administering to the patient a therapeutically effective depot formulation of a pharmaceutically acceptable salt of glatiramer, thereby increasing the patient's tolerability, convenience or adherence to glatiramer treatment.

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