WO2015105757A1 - Fumarate de diméthyle pour traiter une sclérose en plaques - Google Patents

Fumarate de diméthyle pour traiter une sclérose en plaques Download PDF

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Publication number
WO2015105757A1
WO2015105757A1 PCT/US2015/010210 US2015010210W WO2015105757A1 WO 2015105757 A1 WO2015105757 A1 WO 2015105757A1 US 2015010210 W US2015010210 W US 2015010210W WO 2015105757 A1 WO2015105757 A1 WO 2015105757A1
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Prior art keywords
interferon beta
subject
dmf
treatment
methyl
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PCT/US2015/010210
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English (en)
Inventor
Dexiu Annie ZHANG
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Biogen Ma Inc.
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Publication of WO2015105757A1 publication Critical patent/WO2015105757A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

  • the present invention generally relates to methods of treating or preventing a neurological disease or disorder (e.g., multiple sclerosis) in a subject who is not fully responsive to prior treatment with interferon beta (e.g., interferon beta la, interferon beta lb, or both).
  • a neurological disease or disorder e.g., multiple sclerosis
  • interferon beta e.g., interferon beta la, interferon beta lb, or both.
  • MS Multiple sclerosis
  • CNS central nervous system
  • MS An estimated 2,500,000 people in the world suffer from MS. It is one of the most common CNS diseases in young adults, MS is a chronic, progressing, disabling disease, which generally strikes its victims some time after adolescence, with diagnosis generally made between 20 and 40 years of age, although onset may occur earlier. The disease is not directly hereditary, although genetic susceptibility plays a part in its development. MS is a complex disease with heterogeneous clinical, pathological and immunological phenotype.
  • MS characterized by clearly defined relapses with full recover ⁇ ' or with sequelae and residual deficit upon recovery; periods between disease relapses characterized by a lack of disease progression; 2) secondary progressive MS (SP-MS), characterized by initial relapsing remitting course followed by progression with or without occasional relapses, minor remissions, and plateaus; 3) primary progressive MS (PP-MS), characterized by disease progression from onset with occasional plateaus and temporary minor improvements allowed; and 4) progressive relapsing MS (PR-MS), characterized by progressive disease onset, with clear acute relapses, with or without full recovery; periods between relapses characterized by continuing progression.
  • SP-MS secondary progressive MS
  • PP-MS primary progressive MS
  • PR-MS progressive relapsing MS
  • relapsing forms of MS refers to relapsing-remitting MS which is characterized primarily by relapses, and two progressive forms (progressive-relapsing and secondary-progressive) which both have relapsing and progressive characteristics.
  • RR-MS Relapsing-remitting MS
  • RR-MS RR-MS
  • RR-MS RR-MS
  • relapses alternate with periods of clinical inactivity and may or may not be marked by sequelae depending on the presence of neurological deficits between episodes.
  • Periods between relapses during the relapsing-remitting phase are clinically stable.
  • patients with progressive MS exhibit a steady increase in deficits, as defined above and either from onset or after a period of episodes, but this designation does not preclude the further occurrence of new relapses,
  • MS pathology is, in part, reflected by the formation of focal inflammatory demyelinating lesions in the white matter, which are the hallmarks in patients with acute and relapsing disease.
  • the brain is affected in a more global sense, with diffuse but widespread (mainly axonal) damage in the normal appearing white matter and massive demyelination also in the grey matter, particularly, in the cortex.
  • interferon products e.g., Avonex ® , Betaseron ® , and Rebif ®
  • interferon products provide a modest, but important, clinical benefit; they each have demonstrated a mean reduction in relapse rate of approximately 29% to 33% over 2 years.
  • interferon products have acceptable efficacy profiles, they also possess features that reduce patient compliance. For example, administering interferons requires frequent injections and often causes side effects that limit compliance and lead to discontinuation. Moreover, even with full compliance, some patients are not fully responsive to interferon beta treatment s ).
  • TECFTDERATM has been approved by the U.S. Food and Drug Administration for the treatment of patients with relapsing forms of multiple sclerosis (MS).
  • TECFIDERATM contains dimethyl fumarate (DMF), which has the following structure:
  • the starting dose for TECFIDERATM is 120 mg twice a day orally. After 7 days, the dose is to be increased to the maintenance dose of 240 mg twice a day orally. TECFIDERATM can be taken with or without food.
  • One objective of the present invention is to provide a method of treating or preventing of multiple sclerosis in patients who have been treated with interferon beta and are not fully responsive to such treatment(s).
  • the invention provides a method of treating, or preventing a neurological disorder (e.g., multiple sclerosis) in a subject in need thereof, wherein the subject has received prior treatment with interferon beta (e.g., interferon beta la, interferon beta lb, or both).
  • a neurological disorder e.g., multiple sclerosis
  • interferon beta e.g., interferon beta la, interferon beta lb, or both.
  • the method comprises orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of an active agent selected from the group consisting of monomethyl fumarate (“MMF”), a compound that can be metabolized into monomethyl fumarate in vivo (e.g., dimethyl fumarate (“DMF”)), a pharmaceutically acceptable salt thereof, a deuterated analogue thereof, and combinations thereof (collectively "a fumarate agent”), and a pharmaceutically acceptable excipient.
  • MMF monomethyl fumarate
  • DMF dimethyl fumarate
  • a pharmaceutically acceptable salt thereof e.g., a deuterated analogue thereof, and combinations thereof
  • a pharmaceutically acceptable excipient e.g., a pharmaceutically acceptable excipient.
  • the neurological disorder is multiple sclerosis.
  • the subject is not fully responsive to interferon beta treatment.
  • the subject is characterized as a non-responder to interferon beta treatment.
  • interferon beta e.g., interferon beta la, interferon beta lb, or both
  • at least 3 months e.g., at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months.
  • the subject prior to the administration of the pharmaceutical composition comprising the fumarate agent, is characterized by having one or more of the following: (a) having experienced at least one relapse while on interferon beta treatment; (b) having > 6 (e.g., 6, 7, 8, 9, 10, 1 1, 12 etc.) T 2 -hyperinternse lesions; (c) having > 1 (e.g., 1 , 2, 3, 4, 5, etc.) gadolinium- enhancing ("Gd-enhancing”) lesions; and (d) having an unchanged or increased annualized relapse rate upon treatment with interferon beta.
  • the method of treating, or preventing a neurological disease or disorder (e.g., MS) described above is for chronic treatments (e.g., more than 1, 2, 3, 4, 5, 8, 10, or 12 weeks), hi some embodiments, the treatments last for as long as needed (for example, 1 year, 2 years, 5 years, or for the remainder of the patient's life).
  • a neurological disease or disorder e.g., MS
  • chronic treatments e.g., more than 1, 2, 3, 4, 5, 8, 10, or 12 weeks
  • the treatments last for as long as needed (for example, 1 year, 2 years, 5 years, or for the remainder of the patient's life).
  • the subject continues to receive interferon beta treatment after being administered the pharmaceutical composition comprising the fumarate agent. In some embodiments, the subject stops receiving interferon beta treatment after being administered the pharmaceutical composition comprising the fumarate agent.
  • the pharmaceutical composition includes MMF, DMF, or a combination thereof. In some embodiments, the pharmaceutical composition includes DMF. In some embodiments, the only active ingredient in the pharmaceutical composition is DMF.
  • the pharmaceutical composition suitable for the methods described above include without limitation those formulated as an enterically coated immediate release dosage form, a controlled release dosage form (e.g., a delayed release dosage form, a sustained release dosage form, a pulsatile release dosage form), or a combination thereof (e.g., in a kit that contains both types of dosage forms). In some embodiments, the controlled release dosage form is a gastric retentive dosage form. In some embodiments, the pharmaceutical composition is formulated as an enterically coated immediate release dosage form. In some embodiments, the pharmaceutical composition is formulated as a delayed release dosage form.
  • the pharmaceutical composition suitable for the methods described above may also exist without limitation in different forms such as solid dosage forms (e.g., micro-pellets, micro -tablets, a. capsule (such as a soft or hard gelatine capsule), a granule, or a tablet).
  • the fumarate agent (e.g., DMF) in the pharmaceutical composition is in a form of micro-pellets or micro-tablets, in some embodiments, the micro-tablets or micro-pellets are enterically coated.
  • the pharmaceutical composition suitable for the methods described above include without limitation those formulated for once daily (QD) dosing or multiple dosing per day (e.g., twice a day (BID) dosing, three times a day (TTD) dosing).
  • the pharmaceutical composition is formulated for QD dosing, wherein the therapeutically effective amount of a fumarate agent (e.g., DMF) is included in one unit dosage form or provided in a kit containing multiple unit dosage forms.
  • the pharmaceutical composition is formulated for a BID or TID dosing, wherein the therapeutically effective amount of a fumarate agent (e.g., DMF) is divided, for example, equally, for dosing two or three times daily.
  • the therapeutically effective amount of a fumarate agent may be any therapeutically effective dose.
  • the neurological disorder is multiple sclerosis, wherein the therapeutically effective amount of a fumarate agent (e.g., DMF) is an amount that is effective in treating or preventing multiple sclerosis, for example, in a subject who is characterized as a non-responder to interferon beta treatment.
  • the fumarate agent is DMF, and suitable doses of DMF may be any dose from 20 mg to 1 g of DMF.
  • the DMF in the pharmaceutical composition is about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 160 mg, about 200 mg, about 240 mg, about 320 mg, about 360 mg, about 400 mg, about 480 mg, about 600 mg, about 720 mg, about 800 mg, about 900 mg, about 1000 mg of DMF, or any ranges thereof.
  • the therapeutically effective amount of DMF is about 480 mg or about 720 mg per day.
  • the about 480 mg DMF is provided in two unit dosage forms, each comprises about 240 mg DMF and is dosed to a subject about 6 hours to about 12 hours apart in a day.
  • the about 720 mg DMF is provided in three unit dosage forms, each comprises about 240 mg DMF and is dosed to a subject about 4 hours to about 8 hours apart in a day.
  • the therapeutically effective amount of a fumarate agent is an amount that is effective to reduce an annualized relapse rate ("ARR") in a subject treated, for example, by more than 20% (e.g., about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or any ranges thereof) compared to placebo treated subjects.
  • ARR annualized relapse rate
  • the therapeutically effective amount of a fumarate agent is an amount that is effective to reduce the numbers of new or newly enlarging T2 hyperintense lesions in a subject treated, for example, by more than 30% (e.g., about 30, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or any ranges thereof) compared to placebo treated subjects.
  • the therapeutically effective amount of a fumarate agent is an amount that is effective to reduce the numbers of Gd-enhancing lesions in a.
  • the therapeutically effective amount of a fumarate agent is an amount that is effective to reduce the numbers of new non-enhancing Tl hypointense lesions in a subject treated, for example, by more than 30% (e.g., about 30, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or any ranges thereof) compared to placebo treated subjects,
  • Figure ⁇ shows a bar graph comparing the adjusted annualized relapse rates at
  • FIG. 1 shows a bar graph comparing the adjusted mean new or newly enlarging T2 hyperintense lesions at 2 years among placebo treated, 480 nig DMF treated (BID), and 720 mg DMF treated (TXD) groups. All subjects in the three groups are characterized as interferon beta non-responders. Both the BID and TID groups show significantly reduced number of ne or newly enlarging T2 lesions at 2 years compared to placebo treated group.
  • Figure 3 shows a bar graph comparing the mean Gd-enhancing lesions at 2 years among placebo treated, 480 mg DMF treated (BID), and 720 mg DMF treated (TID) groups. All subjects in the three groups are characterized as interferon beta non-responders. Both the BID and TID groups show significantly reduced number of Gd-enhancing lesions at 2 years compared to placebo treated group.
  • Figure 4 shows a bar graph comparing the adjusted mean new non-enhancing
  • DMF dimethyl fumarate
  • MMF monomethyl fumarate
  • a compound that can be metabolized into MMF in vivo includes DMF
  • a compound that can be metabolized into MMF in vivo includes any such compound known in the art.
  • a compound that can be metabolized into MMF in vivo includes, for example, any compound described in U.S. Application No. 13/760,916, the content of which is incorporated herein by reference in its entirety.
  • Compounds that can be metabolized into MMF in vivo include compounds of
  • R 1 and R 2 are independently chosen from hydrogen, C 3 . 6 alkyl, and substituted C3..6 alkyl;
  • R 3 and R 4 are independently chosen from hydrogen, Ci-e alkyl, substituted C
  • R 5 is chosen from methyl, ethyl, and C3.-6 alkyl
  • each substituent group is independently chosen from halogen, -OH, -C , -CF 3 , O. -NQ 2 , benzyl, -C(0)NR 55 2 , - R "nch -OR 55 , -C(0)R 55 , -COOR 11 , and -NR N 2 wherein each R 11 is independently chosen from hydrogen and CM alkyl;
  • R J and R 4 are independently chosen from hydrogen, C e alkyl, and substituted C-._6 alkyl.
  • Useful examples of a compound of Formula (1) include: (N,N- diethylcarbamoyi)niethyl methyl(2E)but-2-ene-l ,4-di endeavour; methyl! N- benzylcarbamoyl]methyl(2E)but-2-ene-l,4-dioate; methyl 2-morphoiin ⁇ 4 ⁇ yi-2- oxoethyl(2E)but-2-ene- 1 ,4-dioate; (N-butylcarbamoyl)methyl methyl(2E)but-2-ene- 1 ,4-dioate; [N-(2-methoxyethyl)carbamoyl]meihyl methyl(2E)but-2-ene- 1 ,4-dioate; 2- ⁇ 2-[(2E)-3 -(meihoxycarbonyl)prop-2-enoyloxy] acetyla
  • Useful examples of a compound of Formula (T) also include: (N,N- diethylcarbamoyl)methyl methyl(2E)but-2-ene-l ,4-dioate; methyl[N- benzylearbamoyl]methyl(2E)but-2-ene- 1 ,4-dioate; methyl 2-morpholin-4-yl-2- oxoethyl(2E)but-2-ene- 1 ,4-dioate; (N-butylcarbamoy l)methyi methyl(2E)but-2-ene- 1,4-dioate; [N-(2-methoxyethyl)carbamoyl]methyl methyl(2E)but-2-ene- 1,4-dioate; 2- (2-[(2E)-3-(metlioxycarbonyl)prop-2-enoyloxy]acetylamino ⁇ acetic acid;
  • R° is chosen from C e alkyl, substituted Cj.e alkyl, Ci- f , heteroalkyl, substituted C;-6 heteroalkyl, C3-8 cycloalkyl, substituted C3-8 cycloalkyl, Ce-s aryl, substituted Ce-s aryl, and -OR 10 wherein R 10 is chosen from Ci- ⁇ alkyl, substituted Cue alkyl, C3.J0 cycloalkyl, substituted C3_jo cycloalkyl, Ce-io aryl, and substituted Ce-io aryl;
  • R ' ' and R s are independently chosen from hydrogen, C-.-c, alkyl, and substituted C-.-c, alkyl;
  • R 9 is chosen from Cue alkyl and substituted Cue alkyl
  • each substituent group is independently chosen from halogen, -OH, -CN, -CF 3 , O. -MO2, benzyl, -C(0)NR n 2 , -R ! ! , -OR 1 ! , -C(0)R n , -COOR 11 , and - R ! ! 2 wherein each R 11 is independently chosen from hydrogen and C1..4 alkyl.
  • Useful examples of a compound of Formula (11) include:
  • Additional usefui examples of a compound of Formula (II) include: methyi(2- methylpropanoyloxy)ethyl(2E)but-2-ene- 1 ,4-dioate; methyl
  • Useful examples of a compound of Formula (II) also include: ethoxycarbonyf oxyethyl methyl(2E)but-2-ene- 1 ,4-dioate; methy3(methyiethoxycaiiionyloxy)ethyl(2E)but-2-ene-l,4--dioate;
  • Compounds that can be metabolized into MMF in vivo also include compounds of Formula ( ⁇ ):
  • R 2 is Ci-Cio alkyl, C5-C15 aryl, hydroxy!, -O-Ci-Cio alkyl, or -O-C5-C15 aryl; each of R J , R 4 , and R 3 , independently, is d-Cw alkyl, C5-C15 aryl, hydroxyl,
  • R 3 is Q-C24 alkyl or Cs-Cjo aryl; each of which can be optionally substituted;
  • each of m, n, and r, independently, is 0-4;
  • Useful examples of a compound of formula (III) include (dimethylsilanediyl)dimethyi difumarate; methyl ((trimethoxysilyi)methyl) fumarate; methyl ((trihydroxysilyl)methyl) fumarate; trimethyl (methylsilaneiriyl) trifumaraie; and a pharmaceutically acceptable salt of any of the foregoing.
  • each of, independently, R 2 and R ⁇ is d-Cjo alkyl or Cs-Cjs aryl.
  • R 2 and R J can be the same or different, can be optionally substituted, and independently can be selected from the group consisting of ( ; -( :,, alkyl or
  • R 1 is C1-C24 alkyl or C5-C50 aryl
  • each of R 7' , R 5 , and R ' ⁇ independently, is hydroxyl, C-. -Cio alkyl, C5-C15 aryl, -O-Cj - Cio alkyl, or -O-C5-C 1 5 aryl;
  • n 1 or 2.
  • Additional compounds that can be metabolized into MMF in vivo include compounds of Formula (VI):
  • R 1 is C C 2 4 alkyl or C 5 -C 50 aryl
  • R 2 is d-Cio alkyl.
  • the term “fumarate agent” refers to MMF, a compound that can be metabolized into MMF in vivo (e.g., DMF), or a pharmaceuiically acceptable salt thereof or combinations thereof, or deuterated analogues thereof.
  • the fumarate agent can include more than one compound, for example, a combination of MMF and DMF.
  • the fumarate agent is a single compound, e.g., DMF.
  • deuterated analogs include compounds of formula (VII): a compound of formula (I)
  • each of R 5 and R 2 is hydrogen, deuterium, deuterated methyl, deuterated ethyl, Ci.e aliphatic, phenyl, 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 -3 heteroatoms independently selected from niirogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and each of R 3 and R 4 , independently, is hydrogen or deuterium, provided that the compound of formula (VII) contains at least one deuterium atom and that R 1 and R 7' are not hydrogen at the same time.
  • Useful examples of compounds of formula (VII) include ( z H 6 )dimethyl fumaric acid ester, (3 ⁇ 4)methyi fumaric acid ester, (3 ⁇ 4)dimethyl fumaric acid ester, dimethyl fumaric(2,3- H 2 ) acid ester, methyl fumaric(2,3 -3 ⁇ 4) acid ester, ethyl fumaric(2,3-T3 ⁇ 4) acid ester, ( ⁇ H ⁇ met yl fumaric(2,3- H 2 ) acid ester, ( 2 3 ⁇ 4)dimethyl fumaric(2,3- ' 3 ⁇ 42) acid ester, methyl (2-moipholino-2-oxoethyl) fumaric(2,3-' i H 2 ) acid ester, methyl (4-morpholino- l -butyl) fumaric(2,3- 2 H2) acid ester, 2- (benzoyl oxy)efhyl methyl fumaric(2,3- 2 H 2
  • treating refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disease or disorder.
  • prophylaxis refers to precluding a patient from getting a disorder, causing a patient to remain free of a disorder for a longer period of time, or halting the progression of a disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art.
  • Interfero -beta or “IFN-beta” includes any interferon-beta protein (e.g., any naturally occurring inierferon-beta protein), whether isolated from a tissue or blood or obtained by a recombinant technique.
  • the inierferon-beia is human interferon-beta.
  • the human interferon beta is recombinantiy produced in mammalian cells.
  • the human inierferon-beta is recombinantiy produced in bacterial cells, such as E. coii.
  • the interferon-beta is interferon-beta la.
  • the interferon beta l a is recombinantiy produced in mammalian cells.
  • the interferon beta la is recombinantiy produced in bacterial cells.
  • the interferon-beta la is selected from Rebif®, Avonex® and CinnoVexTM, which are commercially available forms of interferon- beta la (e.g., Avonex® and Rebif® are marketed in the United States), but other forms are also encompassed.
  • the interferon-beta la is a biosimilar or biogeneric form of Avonex® or Rebif®.
  • the amino acid sequence of the interferon-beta la is at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical or at least 90% identical to the amino acid sequence of natural human interferon-beta la.
  • the amino acid sequence of the interferon- beta la is essentially identical to the amino acid sequence of natural human inierferon-beta l a.
  • the interferon-beta is interferon-beta l b.
  • the interferon-beta lb is recombinantiy produced in bacterial cells (e.g., modified E. coll).
  • the interferon-beta lb is recombinantiy produced in mammalian cells.
  • the amino acid sequence of the interferon-beta l b is at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical or at least 90% identical to the amino acid sequence of natural human interferon-beta 1 b.
  • the amino acid sequence of the interferon-beta lb is essentially identical to the amino acid sequence of natural human interferon-beta lb.
  • the interferon-beta lb is selected from Betaseron®
  • interferon-beta lb (also referred to as Betaferon®), Extavia® and ZIFERON®, which are commercially available forms of interferon -beta lb (e.g., Betaseron ⁇ is marketed in the United States), but other forms are also encompassed.
  • the interferon- beta lb is a biosimilar or biogenetic form of Betaseron 1 ®, Extavia® or ZIFERON®.
  • interferon-beta Modified forms of interferon-beta are also encompassed by the term interferon -beta.
  • an interferon-beta can be modified by deleting, adding or substituting an amino acid.
  • Betaseron ⁇ the native protein has been modified by a C17S mutation.
  • Other modifications include attachment of another protein or other chemical entities to the interferon-beta., e.g., those chemical residues which increase the water-solubility of the interferon-beta, such as straight or branched polyethylene glycol (PEG) or polypropylene glycol (PPG) moieties, and the like.
  • PEG polyethylene glycol
  • PPG polypropylene glycol
  • the interferon-beta is pegylated interferon-beta. In some embodiments, the interferon-beta is pegylated interferon-beta la (e.g., PLEGRIDYTM). In some embodiments, the interferon-beta is pegylated interferon- beta lb.
  • interferon beta treatment(s) refers to treatments ) of a subject with interferon beta according to art recognized doses and dosing regimen for the interferon beta.
  • interferon beta treatment using interferon beta la refers to administering interferon beta la in a manner consistent with an FDA (or other similarly situated agencies in the U.S. or worldwide) approved label (e.g., the label approved for Avonex®).
  • interferon beta treatment using interferon beta lb e.g., Betaseron® refers to administering interferon beta lb in a manner consistent with an FDA (or other similarly situated agencies in the U.S. or worldwide) approved label (e.g., the label approved for Betaseron® ) ).
  • terapéuticaally effective dose and “therapeutically effective amount” refer to that amount of a compound which results in prevention or delay of onset or amelioration of symptoms of a neurological disorder in a. subject or an attainment of a desired biological outcome, such as reduced neurodegeneration (e.g., demyelination, axonai loss, or neuronal death) or slowing in the accumulation of physical disability (e.g., as indicated by, e.g., a reduced rate of worsening of a clinical score (e.g., Enhanced Disability Status Scale ("EDSS”)) or another suitable parameter indicating disease state.
  • EDSS Enhanced Disability Status Scale
  • Exemplar ⁇ ' disease state parameters include the number of clinical relapses, number of Tl lesions, reduced mean number of new and total gadolinium-enhancing (Gd+) lesions on brain MRI scans, number and volume of new or newly-enlarging T2 hyperintense lesions, number of new Tl hypointense lesions, percentage of Gd+ lesions that convert to Tl kypointense lesions, measures of atrophy and magnetization transfer ratio, and the like).
  • Gd+ gadolinium-enhancing
  • microtablet means a compact in the form of a small (micro) tablet having a mean diameter of less than 5,000 microns (e.g., about 1 ,000 microns to about 3,000 microns), excluding any coating, that comprises the active ingredient(s) and one or more excipients.
  • the active ingredient(s) and excipients can be homogeneously or heterogeneously mixed in the microtablet.
  • the microtablets may be coated, for example, by a seal coating, an enteric coating, or a combination thereof.
  • an object e.g., a microtablet
  • a coating it is to be understood that the object can be fully or partially coated by one or more coatings.
  • an object e.g., a microtablet
  • the object can be fully or partially encapsulated.
  • subject generally refers to human, including healthy human or a patient with certain diseases or disorders (e.g., MS).
  • diseases or disorders e.g., MS
  • the invention provides a method of treating or preventing a neurological disease or disorder (e.g., MS) in a subject who is not fully responsive to prior interferon beta treatment(s), the method comprises orally administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a. fumarate agent and a pharmaceutically acceptable excipient.
  • a neurological disease or disorder e.g., MS
  • a pharmaceutical composition comprising a therapeutically effective amount of a. fumarate agent and a pharmaceutically acceptable excipient.
  • the neurological disease or disorder is an autoimmune disease. In some embodiments, the neurological disease or disorder is a demyelinating disease or disorder.
  • the neurological disease or disorder is selected from the group consisting of multiple sclerosis (MS), Huntington's disease, Alzheimer's disease, Parkinson's disease, optic neuritis, Devic disease, transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodys trophy and adrenomyeioneuropathy, acute inflammatory demyelinating polyneuropathy (AIDP), chronic inflammatory demyelinating polyneuropathy (CIDP), acute transverse myelitis, progressive multifocal ieueoeneephaiopathy (PML), acute disseminated encephalomyelitis (ADEM) and oilier hereditary disorders, such as leukodystrophies, Leber's optic atrophy, and Charcot-Marie-Tooth disease.
  • MS multiple sclerosis
  • Huntington's disease Huntington's disease
  • Alzheimer's disease Alzheimer's disease
  • Parkinson's disease optic neuritis
  • Devic disease Devic disease
  • transverse myelitis
  • the neurological disease or disorder is multiple sclerosis.
  • the MS is relapsing remitting MS, secondary progressive MS, primary progressive MS, progressive relapsing MS, or clinically isolated syndrome (CIS).
  • the neurological disease or disorder is a relapsing form of MS.
  • the subject is not fully responsive to prior interferon beta l a (e.g., Avonex ⁇ ) treatment, prior interferon beta lb (e.g., Betaseron®, Extavia ⁇ or Ziferon®) treatment, or both.
  • prior interferon beta lb e.g., Betaseron®, Extavia ⁇ or Ziferon®
  • the subject is initially responsive to interferon beta treatment and becomes not fully responsive to interferon beta treatment.
  • the subject is initially not fully responsive and stays not fully responsive to interferon beta treatment.
  • a subject treated with interferon beta may be characterized as not fully responsive to the treatment if the subject experiences deterioration or essentially no improvement of clinical symptoms of diseases, e.g., the subject continues to experience one or more relapses, has no improvement (or worsening) of EDSS scores, has no improvement (or worsening) as determined by MR! measurement of biomarkers (e.g., number and/or volume of new or enlarging T2 lesions, number and/or volume of new Tl lesions, number of new Gd-enhancing lesions, or a combination thereof), or a combination thereof.
  • Other methods such as genetic profiling may also be used for identifying subjects who are not fully responsive to interferon beta treatment(s).
  • the subject is not fully responsive to prior interferon beta treatments is characterized as a non-responder to interferon beta treatments.
  • Non-responders to interferon beta treatments include those who have been treated with interferon beta (e.g., interferon beta, la, interferon beta lb, or a combination thereof) for at least 3 months (e.g., at least 4 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months) and experience deterioration or essentially no improvement of clinical symptoms of diseases.
  • a non-responder received interferon beta treatment within one year of commencement of administering the pharmaceutical composition comprising the fumarate agent.
  • a non-responder to interferon beta treatments is characterized by having one or more of the following: (a) having experienced at least one relapse while on interferon beta treatment; (b) having > 6 (e.g., 6, 7, 8, 9, 10, 1 1, 12 etc.) T 2 -hyperintense lesions; (c) having > 1 (e.g., 1, 2, 3, 4, 5, etc.) gadolinium- enhancing ("Gd-enhancing") lesions; and (d) having an unchanged or increased annualized relapse rate upon treatment with interferon beta.
  • Gd-enhancing gadolinium- enhancing
  • the non-responder has been treated with interferon beta
  • the non-responder is further characterized by having 6 or more than 6 (e.g., 9 or more than 9) T2-hyperinten.se lesions or having one or more than one Gd-enhancing lesions.
  • the non-responder has been treated with interferon beta (e.g., interferon beta la, interferon beta lb, or both) for at least 6 months and has an unchanged or increased annualized relapse rate upon treatment with interferon beta.
  • the annualized relapse rate in the first year prior to the administration of the fumarate agent is the same as or greater than the annualized relapse rate in the second year prior to the administration of the fumarate agent.
  • the non-responder has been treated with interferon beta
  • the non-responder is further characterized by having 6 or more than 6 (e.g., 9 or more than 9) T2-hyperintense lesions or having one or more than one Gd-enhancing lesions.
  • the non-responder has been treated with interferon beta (e.g., interferon beta l a, interferon beta lb, or a combination thereof) for at least 12 months and has an unchanged or increased annualized relapse rate upon treatment with interferon beta, compared with the year prior to the treatment with interferon beta.
  • the annualized relapse rate in the first year prior to the administration of an fumarate agent is the same or greater than the annualized relapse rate in the second year prior to the administration of the fumarate agent.
  • a non-responder to interferon beta treatments is a patient that has received 12 months or more of interferon beta treatment and experienced (a) at least 1 relapse while on treatment and 9 or more T2-hyperintense or 1 or more gadolinium-enhancing lesions, or (b) an unchanged or increased relapse rate irs 12 or more months on interferon beta compared with the 2 years preceding treatment with the interferon beta.
  • compositions suitable for the methods described herein include those contain a. therapeutically effective amount of a fumarate agent.
  • the pharmaceutical composition comprises MMF, DMF, or a combination thereof.
  • the pharmaceutical composition comprises DMF.
  • the only active ingredient in the pharmaceutical composition is DMF.
  • the pharmaceutical composition for treating Interferon beta non-responders is Tecfidera® which is a eontroll ed-release microtablet formulation containing 240 mg of DMF per capsule and is given to a patient twice daily or three times daily.
  • a Teelklera ' ⁇ ⁇ ⁇ capsule is given to a patient twice daily for a total daily dose of 480 mg.
  • the pharmaceutical composition herein may be in different forms.
  • Non- limiting examples include pills, tablets, microtablets, pellets, powders, granules, micropellets, capsules (e.g., containing microtablets), liquid formulations for oral administration, and the form of dietary supplements.
  • Methods for preparing pharmaceutical compositions in these forms are known in the art.
  • Suitable pharmaceutically acceptable excipients for preparing the pharmaceutical compositions are also known in the art, for example, binders, fillers, disintergrants, glidants, lubricants, diluents, plasticizers, etc. as described in Remington's Pharmaceutical Science, 18 th Edition, 1990, Mack Publishing Company, Easton, Pa ("Remington's").
  • the pharmaceutical composition is in the form of a capsule (such as a soft or hard gelatine capsule) containing DMF in the form of microtablets or micropellets (e.g., enteric-coated microtablets or micropellets).
  • Suitable microtablets or micropellets are, without limitation, those having a mean diameter of 5,000 microns or less (e.g., 4,000 microns or less, 3,000 microns or less, 2,000 microns or less, 1,000 microns or less, or 500 microns or less) exclusive of any optional coating applied to the microtablets or micropellets.
  • the pharmaceutical composition is in the form of a capsule containing a pharmaceutical preparation consisting essentially of 60-240 mg (e.g., 120 mg, or 240 nig) of DMF in the form of enteric-coated micro tablets.
  • the mean diameter of such microtablets is 1 ,000-5,000 microns, e.g., 1,000-3,000 microns or 2,000 microns.
  • Methods for preparing microtablets or micropellets (e.g., enteric- coated microtablets or micropellets) comprising DMF are known in the art, for example, as described in U.S. Patent No. 6,509,376 and incorporated by reference in its entirety herein.
  • the pharmaceutical composition suitable for the methods described above include without limitation those formulated as an enterically coated immediate release dosage form, or a controlled release dosage form (e.g., a delayed release dosage form, a sustained release dosage form, a pulsatile release dosage form).
  • the controlled release dosage form is a gastric retentive dosage form.
  • the pharmaceutical composition is formulated as an enterically coated immediate release dosage form.
  • the pharmaceutical composition is formulated as a delayed release dosage form.
  • the fumarate agent e.g., DMF, MMF, or a combination thereof
  • Such formulation can be prepared by various technologies by a skilled person in the art.
  • the formulation can contain the therapeutic compound, a rate-controlling polymer (i.e., a material controlling the rate at which the therapeutic compound is released from the dosage form) and optionally other excipients.
  • rate-controlling polymers are hydroxy alkyl cellulose, hydroxypropyl alkyl cellulose (e.g., hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, hydroxypropyl isopropyl cellulose, hydroxypropyl butyl cellulose and hydroxypropyl hexyl cellulose), poly(ethySene)oxide, alkyl cellulose (e.g., ethyl cellulose and methyl cellulose), carboxymefhyl cellulose, hydrophilic cellulose derivatives, and polyethylene glycol, compositions, e.g., those described in WO 2006/037342, incorporated herein by reference.
  • the pharmaceutical composition suitable for the methods described above include without limitation those formulated for once daily (QD) dosing or multiple dosing per day (e.g., twice a day (BID) dosing, three times a day (TID) dosing).
  • the pharmaceutical composition is formulated for QD dosing, wherein the therapeutically effective amount of fumarate agent (e.g., DMF) is included in one unit dosage form or provided in a kit containing multiple unit dosage forms.
  • the pharmaceutical composition is formulated for a BID or TID dosing, wherein the therapeuticaliy effective amount of fumarate agent (e.g., DMF) is divided, for example, equally, for the two or three dosing.
  • the pharmaceutical composition may be administered with or without food.
  • the pharmaceutical composition comprising a fumarate agent e.g., DMF
  • a fumarate agent e.g., DMF
  • the pharmaceutical composition comprising a fumarate agent is administered with food, for example, to reduce flushing.
  • the neurological disorder is multiple sclerosis
  • the therapeutically effective amount of a fumarate agent e.g., DMF
  • the therapeutically effective amount can range from about 1 mg/kg to about 50 mg/kg (e.g., from about 2.5 mg kg to about 20 mg/kg or from about 2.5 mg kg to about 15 mg kg). Effective doses will vary, as recognized by those skilled in the art, dependent on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents.
  • an effective daily dose of DMF or MMF to be administered to the subject can be from about 20 mg to about 1 g, for example, from about 100 mg to about 800 mg (e.g., from about 120 mg to about 720 mg, from about 240 mg to about 720 mg: or from about 480 mg to about 720 mg; or about 720 mg).
  • An effective daily dose of DMF or MMF can also be, for example, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 160 mg, about 200 mg, about 240 mg, about 320 mg, about 360 mg, about 400 mg, about 480 mg, about 600 mg, about 720 mg, about 800 mg, about 900 mg, about 1000 mg of DMF or MMF, or any ranges thereof.
  • the dosages may be administered one or more times per day.
  • a 720 mg daily dose may be administered all at once or in separate administrations of 2, 3, 4, 5 or 6 (e.g., equal) doses.
  • a 480 mg daily dose may be administered ail at once or in separate administrations of 2, 3, 4, 5 or 6 (e.g., equal) doses.
  • the therapeutically effective dose of DMF or MMF is about 480 mg per day, effected by two equal, separate administrations, i.e., 240 mg per administration, at about 6 to about 12 hours apart in a day.
  • the therapeutically effective dose of DMF or MMF is about 720 mg per day, effected by three equal, separate administrations, i.e., 240 mg per administration, at about 4 to about 8 hours apart in a day. In some embodiments, the therapeutically effective dose of DMF or MMF is 300 mg to 1000 mg per day. In some embodiments, the therapeutically effective dose of DMF or MMF is 300 mg to 1000 mg per day delivered once daily. In some embodiments, the therapeutically effective dose of DMF or MMF is about 720 mg per day delivered once daily. In some embodiments, the therapeutically effective dose of DMF or MMF is about 480 mg per day delivered once daily.
  • a method according to the invention comprises orally administering a dosage form that provides a total amount of about 60 mg to about 1000 mg of DMF.
  • the dosage form can, for example, contain a total amount of DMF effective for treatment or prophylaxis of multiple sclerosis.
  • the effective amount can range, but is not limited to, a.
  • the dosage form can contain, but is not limited to, a total amount of DMF of about 60 mg DMF, about 80 mg DMF, about 100 mg DMF, about 120 mg DMF, about 140 mg DMF, about 160 mg DMF, about 180 mg DMF, about 200 mg DMF, about 220 mg DMF, about 240 mg DMF, about 260 mg DMF, about 280 mg DMF, about 300 mg DMF, about 320 mg DMF, about 340 mg DMF, about 360 mg DMF, about 380 mg DMF, about 400 mg DMF, about 420 mg DMF, about 450 mg DMF, about 480 mg DMF, or about 500 mg DMF.
  • DMF is the only active ingredient in the dosage form.
  • MMF in vivo include any amount of the compound that is equivalent to the amount of DMF or MMF described above based on fumaric acid content,
  • Therapeutically effective amount of a fumarate agent may also be any amount of the fumarate agent which results in prevention or delay of onset or amelioration of symptoms of a neurological disorder in a subject or an attainment of a desired biological outcome, such as reduced neurodegenerat on (e.g., demyelination, axonaf loss, or neuronal death) or slowing in the accumulation of physical disability.
  • a desired biological outcome such as reduced neurodegenerat on (e.g., demyelination, axonaf loss, or neuronal death) or slowing in the accumulation of physical disability.
  • the therapeutically effective amount of a fumarate agent is an amount that is effective to reduce an annualized relapse rate ("ARR") in a subject treated, for example, by more than 20% (e.g., about 20%, about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, or any ranges thereof) compared to placebo treated subjects.
  • ARR annualized relapse rate
  • the therapeutically effective amount of a fumarate agent is an amount that is effective to reduce the numbers of new or newly enlarging T2 hyperintense lesions in a subject treated, for example, by more than 30% (e.g., about 30, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or any ranges thereof) compared to placebo treated subjects.
  • the therapeutically effective amount of a fumarate agent is an amount that is effective to reduce the numbers of Gd-enhancing lesions in a subject treated, for example, by more than 30% (e.g., about 30, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or any ranges thereof) compared to placebo treated subjects.
  • the therapeutically effective amount of a fumarate agent is an amount that is effective to reduce the numbers of new non-enhancing Tl hypointense lesions in a subject treated, for example, by more than 30% (e.g., about 30, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or any ranges thereof) compared to placebo treated subjects.
  • DMF is known to cause flushing and gastrointestinal (GI) side effects in certain patients. While the side effects generally subside soon after patients start on the treatment, the starting dose is 120 mg DMF BID orally for the first 7 days. The dose can be increased to the effective dose of 240 mg DMF BID (i.e., 480 mg DMF per day). For those patients who experience GI or flushing side effects, taking DMF with food can improve toferability.
  • the method described herein comprises administering to the subject a first dose of the pharmaceutical composition for a first dosing period; and administering to the subject a second dose of the pharmaceutical composition for a second dosing period.
  • the first dosing period is at least one week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks etc.).
  • the first dose of the pharmaceutical composition comprises about 120 mg of dimethyl fumarate and the first dose is administered to the patient twice per day (BID) or three times per day (TID) for the first dosing period.
  • the second dose of the pharmaceutical composition comprises about 240 mg of dimethyl fumarate and the second dose is administered to the patient three times per day (TID) for the second dosing period.
  • the second dose of the pharmaceutical composition comprises about 240 mg of dimethyl fumarate and the second dose is administered to the patient two times per day (BID) for the second dosing period.
  • the subject if the subject experiences flushing or a gastrointestinal disturbance during the second dosing period, then the subject is administered a. dose of the pharmaceutical composition comprising about 120 mg of dimethyl fumarate twice per day (BID) or three times per day (TID) for a period of from 1 week to I month.
  • the only active ingredient in the first and second dose of the pharmaceutical composition is DMF.
  • the first dose of the pharmaceutical composition comprises about 120 mg of the fumarate agent and the pharmaceutical composition is administered to the subject once daily for at least one week
  • the second dose of the pharmaceutical preparation comprises about 240 mg of the fumarate agent and the pharmaceutical composition is administered to the subject once daily for at least two weeks.
  • the subject is administered a first dose for one week and a second dose for a second dosing period of at least 48 weeks. In another embodiment, the subject is administered a. first dose for one week and a second dose for a second dosing period of at least two years. In another embodiment, the subject is administered a first dose for one week and a second dose until the subject does not require treatment or prophylaxis of the disease or disorder (e.g., neurodegenerative disorder).
  • the disease or disorder e.g., neurodegenerative disorder
  • the method described herein further comprises administering to the subject one or more non-steroidal anti-inflammatory dmgs (e.g., aspirin) before (for example, 10 minutes to an hour, e.g., 30 minutes before) administering the pharmaceutical composition comprising the fumarate agent.
  • the subject administered the pharmaceutical composition comprising the fumarate agent takes the one or more non-steroidal anti-inflammatory drugs (e.g., aspirin) to reduce flushing.
  • the one or more non-steroidal anti-inflammatory drugs is selected from a group consisting of aspirin, ibuprofen, naproxen, ketoprofen, celecoxib, and combinations thereof.
  • the one or more nonsteroidal anti-inflammatory dmgs can be administered in an amount of about 50 mg to about 500 mg before taking the dosage form described above.
  • a patient takes 325 mg aspirin before taking the pharmaceutical composition comprising the fumarate agent.
  • RRMS diagnosis (McDonald criteria), and EDSS score 0-5.0.
  • the odds of having more Gd+ lesions was analyzed using ordinal logistic regression adjusted for study, region, and baseline number of Gd+ lesions.
  • the mean number of ne or enlarging T2- hyperintense lesions was analyzed using negative binomial regression adjusted for study, region, and baseline T2-hypcrintense volume).
  • the mean number of new non- enhancing Tl -hypointense lesions was analyzed using negative binomial regression adjusted for study, region, and baseline volume of Tl -hypointense lesions.
  • T 2 Hyperin tense Lesions Over 2 years in this subgroup, a mean of 17.0 new or newly enlarging T 2 hyperintense lesions developed in placebo group, compared with a mean of 4.3 and 5.7 in BID and TID respectively. The median number of new/enlarging T 2 lesions that developed over 2 years was 7.0 in the placebo group and 1.0 and 2.0 for BID and TID respectively. The adjusted mean ratios obtained from the model were 0.15 (pO.0001) for BID vs. placebo, and 0.24 (pO.0001) for TID vs. placebo. This indicated that BID and TID reduced the number of new/enlarging T 2 lesions that developed over 2 years by 85% and 76% respectively compared with placebo (see Figure 2).
  • Gd-Eiihancing Lesions At 2 years, the mean number of Gd-enhancing lesions in the placebo group was 3.0, compared with 0.1 and 0.5 in the BID and TID groups respectively.
  • the odds ratios obtained from the model were 0.20 (95% CI, 0.07, 0.58, 0.003 1 ! for BID vs. placebo and 0.43 (95% CI, 0.19, 0.96, p 0.0401 ⁇ for TID vs. piacebo. This indicated that Treatment with BID and TID resulted in statistically significant reductions over placebo of 80% and 57% respectively, in the odds of having greater Gd-enhancing lesion activity at 2 years (see Figure 3).
  • Example 1 The same post-hoc analysis as shown in Example 1 was done to evaluate the efficacy of dimethyl fumarate in relapsing remitting multiple sclerosis patients who were characterized as "non-responders" to prior treatment with interferon beta ( ⁇ ⁇ ), except that different criteria for characterizing IFN non-responders were used. The results are shown in Tables 2-5.
  • IFN non-resp nders definition 2 Part b: on
  • Rate ratro (active/placebo) (95% CI) (b) 0.571 (0,369,0.839) 0.463 (0.314,0.698) p-value (b) 0.0043 0.0002
  • region study, and number of relapses in the 1 year prior to study entry.

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Abstract

L'invention concerne un procédé pour traiter ou prévenir une maladie ou trouble neurologique (par exemple, une sclérose en plaques) chez un sujet en ayant besoin, comprenant l'administration orale au sujet d'une composition pharmaceutique comprenant une quantité thérapeutiquement efficace d'un principe actif choisi dans le groupe constitué par fumarate de diméthyle, un composé qui peut être métabolisé en fumarate de diméthyle in vivo, un sel pharmaceutiquement acceptable de celui-ci, un analogue deutéré de celui-ci, et des combinaisons de celui-ci, et un excipient pharmaceutiquement acceptable, le sujet n'étant pas pleinement réactif à un traitement d'interféron bêta.
PCT/US2015/010210 2014-01-07 2015-01-06 Fumarate de diméthyle pour traiter une sclérose en plaques WO2015105757A1 (fr)

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US9517209B2 (en) 2014-02-28 2016-12-13 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
US10918616B2 (en) 2014-02-28 2021-02-16 Banner Life Sciences Llc Fumarate ester pharmaceutical compositions
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US10098863B2 (en) 2014-02-28 2018-10-16 Banner Life Sciences Llc Fumarate esters
US9820961B2 (en) 2015-08-31 2017-11-21 Banner Life Sciences Llc Fumarate ester dosage forms
US10105335B2 (en) 2015-08-31 2018-10-23 Banner Life Sciences Llc Fumarate ester dosage forms
US9814692B2 (en) 2015-08-31 2017-11-14 Banner Life Sciences Llc Fumarate ester dosage forms
US9636318B2 (en) 2015-08-31 2017-05-02 Banner Life Sciences Llc Fumarate ester dosage forms
US9636319B1 (en) 2015-08-31 2017-05-02 Banner Life Sciences Llc Fumarate ester dosage forms
US9566259B1 (en) 2015-08-31 2017-02-14 Banner Life Sciences Llc Fumarate ester dosage forms
US10945985B2 (en) 2015-08-31 2021-03-16 Banner Life Sciences Llc Fumarate ester dosage forms
US11590095B2 (en) 2015-08-31 2023-02-28 Banner Life Sciences Llc Fumarate ester dosage forms
EP3368030A4 (fr) * 2015-10-28 2019-05-01 Sun Pharmaceutical Industries Limited Compositions pharmaceutiques de fumarate de diméthyle
US11903918B2 (en) 2020-01-10 2024-02-20 Banner Life Sciences Llc Fumarate ester dosage forms with enhanced gastrointestinal tolerability
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