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EP-3600553-B1 - GLATIRAMER DEPOT SYSTEMS FOR TREATING PROGRESSIVE FORMS OF MULTIPLE SCLEROSIS

EP3600553B1EP 3600553 B1EP3600553 B1EP 3600553B1EP-3600553-B1

Inventors

  • DANON, Uri
  • BLEICH KIMELMAN, Nadav
  • POPPER, Laura
  • MAROM, EHUD

Dates

Publication Date
20260506
Application Date
20180325

Claims (14)

  1. A sustained release depot formulation comprising a therapeutically effective amount of a pharmaceutically acceptable salt of glatiramer for use in 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, wherein the depot formulation is administered or implanted to the patient.
  2. The depot formulation for use according to claim 1, wherein the patient: (i) has been diagnosed with PPMS for at least 1 year and a sustained increment of ≥ 1 point in the EDSS score in the last year; (ii) has an EDSS score between 2 and 5.5, inclusive (Pyramidal or Cerebellar FS ≥ 2); (iii) has a documented history of, or the presence of more than 1 oligoclonal band (OCB) if quantitative testing was done, or OCB+ if no quantitative testing was done, and/or positive IgG index in the cerebrospinal fluid (CSF); (iv) has at least 1 gadolinium-enhancing lesion on MRI and/or at least 1 gadolinium-enhancing lesion documented within the previous year on MRI; or (v) any combination of (i) to (iv).
  3. The depot formulation for use according to claim 1 or claim 2, wherein the symptom is selected from the group consisting of impaired walking capability, weakness of the leg, stiffness of the leg, impaired balance, impaired coordination, impaired memory, impaired cognitive function, a difficulty to swallow, impaired vision, general fatigue, pain, impaired bladder function, impaired bowel function, and any combination thereof.
  4. The depot formulation for use according to any one of claims 1 to 3, wherein treating PPMS or SPMS comprises: (i) increasing the time to onset of 12 week Confirmed Disease Progression (CDP) of the patient assessed by Expanded Disability Status Scale (EDSS), compared to baseline or untreated control; (ii) decreasing whole brain volume change or cortical volume change of the patient, compared to baseline or untreated control; (iii) decreasing the time needed for the patient to complete a timed 25-foot walk (T25FW) test, compared to baseline or untreated control; (iv) decreasing the time needed for the patient to complete a 9-Hole Peg Test (9-HPT), compared to baseline or untreated control; (v) decreasing the number of new or enlarging T2 lesions in the brain of the patient, compared to baseline or untreated control; (vi) decreasing the volume of T2 lesions in the brain of the patient, compared to baseline or untreated control; (vii) decreasing the number of new or enlarging T1 lesions in the brain of the patient, compared to baseline or untreated control; (viii) decreasing the volume of T1 lesions in the brain of the patient, compared to baseline or untreated control; (ix) decreasing the number or volume of Gadolinium (Gd) lesions in the brain of the patient, compared to baseline or untreated control; (x) reducing the rate of progression of PPMS or SPMS, compared to baseline or untreated control; (xi) preventing further progression of PPMS or SPMS, compared to baseline or untreated control; or (xii) any combination of (i) to (xi).
  5. The depot formulation for use according to claim 4, wherein the patient has an EDSS score of <5.5 and CDP is at least a 1 point increase of the EDSS score; or wherein the patient is having an EDSS score of 5.5-10 and CDP is at least a 0.5 point increase of the EDSS score.
  6. The depot formulation for use according to claim 4 or claim 5, wherein the baseline is a period of 12 weeks or more prior to treatment by the depot formulation, preferably wherein the baseline is a period of 1 year prior to treatment by the depot formulation.
  7. The depot formulation for use according to any one of claims 1 to 6, wherein the depot formulation is administered or implanted systemically, preferably wherein the depot formulation is administered or implanted intramuscularly, subcutaneously, percutaneously, intravenously, or by inhalation, more preferably wherein the depot formulation is administered or implanted intramuscularly.
  8. The depot formulation for use according to any one of claims 1 to 7, wherein the depot formulation comprises 10 mg to 100 mg of the pharmaceutically acceptable salt of glatiramer, preferably wherein the depot formulation comprises 40 mg to 80 mg dose of the pharmaceutically acceptable salt of glatiramer, more preferably wherein the depot formulation comprises a 40 mg dose of the pharmaceutically acceptable salt of glatiramer or wherein the depot formulation comprises a 80 mg dose of the pharmaceutically acceptable salt of glatiramer.
  9. The depot formulation for use according to any one of claims 1 to 8, wherein the depot formulation is administered in a therapeutically effective regime of once every 1 to 15 weeks, preferably wherein the depot formulation is administered once every 4 weeks and/or wherein the depot formulation is repeatedly administered during 1 year or more.
  10. The depot formulation for use according to any one of claims 1 to 9, wherein the pharmaceutically acceptable salt of glatiramer is glatiramer acetate (GA).
  11. The depot formulation for use according to any one of claims 1 to 10, wherein the depot formulation comprises 20% to 30% solids.
  12. The depot formulation for use according to any one of claims 1 to 11, wherein the depot formulation comprises a Poly(Lactide-co-Glycolide) (PLGA) copolymer, preferably wherein the PLGA copolymer is a poly(D,L-lactide-co-glycolide) (50:50) copolymer, more preferably wherein the depot formulation comprises 550 mg PLGA copolymer per 40 mg of the pharmaceutically acceptable salt of glatiramer and/or wherein the PLGA copolymer at least partly encapsulates the pharmaceutically acceptable salt of glatiramer.
  13. The depot formulation for use according to any one of claim 1 to 12, wherein the depot formulation, in phosphate buffered saline (PBS, pH 7.4), in a closed vial, at 37°C, during stirring: (i) releases about 15% to about 30% of the glatiramer salt within 1 week; (ii) releases about 30% to about 50% of the glatiramer salt within 2 weeks; (iii) releases about 50% to about 90% of the glatiramer salt within 3 weeks; (iv) releases about 90% to about 100% of the glatiramer salt within 4 weeks; or (v) any combination of (i) to (iv).
  14. The depot formulation for use according to claim 13, 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.

Description

FIELD OF THE INVENTION The present invention relates to depot formulations for prolonged release of glatiramer acetate or other pharmaceutically acceptable salts of glatiramer for treating primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS). BACKGROUND OF THE INVENTION Copolymer-1, also known as glatiramer acetate (GA) and marketed under the tradename Copaxone®, comprises the acetate salts of random copolymers 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 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 is 5,000-9,000 Daltons. Glatiramer acetate is sold in USA as Copaxone®, indicated for reduction of the frequency of relapses in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). Copaxone® has been approved since 1996 for treating relapsing-remitting multiple sclerosis (RRMS) at a dose of 20 mg administered by daily subcutaneous injections. Since 2014, Copaxone® has also been approved at a dose of 40 mg administered by three injections per week, performed at least 48 hours apart. Compared to daily administration of Copaxone® in the 20 mg dose, the latter dose and regime reduce the yearly number of injections by about 200, while maintaining the same efficacy. Daily and thrice-weekly Copaxone® treatments involve self-injection of the active substance. Frequently observed injection-site problems include irritation, hypersensitivity, inflammation, pain and even necrosis (in the case of interferon 1β treatment) and consequent problems in patient compliance. Side effects generally include a lump at the injection site (injection site reaction), aches, fever, and chills. These side effects are generally mild in nature. Occasionally a reaction occurs minutes after injection in which there is flushing, shortness in breath, anxiety and rapid heartbeat. These side effects subside within thirty minutes. Over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, may develop. Therefore, an alternative method of administration is desirable. Several serious side effects have been reported for glatiramer acetate, according to the FDA's prescribing label, these include serious side effects to the body's cardiovascular system, digestive system (including liver), hemic and lymphatic system, musculoskeletal system, nervous system, respiratory system, special senses (in particular the eyes), urogenital system; also reported have been metabolic and nutritional disorders; however a link between glatiramer acetate and these adverse effects has not been definitively established (FDA Copaxone® label). The parenteral route by intravenous (IV), intramuscular (IM), or subcutaneous (SC) injection is the most common and effective form of delivery for small as well as large molecular weight drugs. However, pain, discomfort and inconvenience due to needle sticks makes this mode of drug delivery the least preferred by patients. Therefore, any drug delivery technology that can at a minimum reduce the total number of injections is preferred. Such reductions in frequency of drug dosing in practice may be achieved through the use of injectable depot formulations that are capable of releasing drugs in a slow but predictable manner and consequently improve compliance. For most drugs, depending on the dose, it may be possible to reduce the injection frequency from daily to once or twice monthly or even longer (6 months). In addition to improving patient comfort, less frequent injections of drugs in the form of depot formulations have been shown to reduce unwanted events, such as immunogenicity etc. often associated with large molecular weight drugs. Microparticles, implants and gels are the most common forms of biodegradable polymeric devices used in practice for prolonging the release of drugs in the body. Microparticles are suspended in an aqueous media right before injection and one can load as much as 40% solids in suspensions. Implant/rod formulations are delivered to SC/IM tissue with the aid of special needles in the dry state without the need for an aqueous media. This feature of rods/implants allows for higher masses of formulation, as well as drug content to be delivered. Further, in the rods/implants, the initial burst problems are minimized due to much smaller area in implants compared to the microparticles. Besides biodegradable systems, there are non-biodegradable implants and infusion pumps that can be worn outside the body. Non-biodegradable implants require a doctor's visit not only for implanting the device into the SC/IM tissue but also to remove them after the drug release period. Injectable composi