WO2012162669A1 - Methods of treating multiple sclerosis and preserving and/or increasing myelin content - Google Patents
Methods of treating multiple sclerosis and preserving and/or increasing myelin content Download PDFInfo
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- WO2012162669A1 WO2012162669A1 PCT/US2012/039721 US2012039721W WO2012162669A1 WO 2012162669 A1 WO2012162669 A1 WO 2012162669A1 US 2012039721 W US2012039721 W US 2012039721W WO 2012162669 A1 WO2012162669 A1 WO 2012162669A1
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Classifications
-
- 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
- A61K31/225—Polycarboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- 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
Definitions
- the subject has multiple sclerosis, such as relapsing-remitting multiple sclerosis, and is administered about 480 mg per day of a fumarate (e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereof) for a period of time sufficient to achieve one or more of the following changes: (a) reduced frequency of relapse in the subject; (b) reduced probability of relapse in the subject; (c) reduced annualized relapse rate in the subject; (d) reduced risk of disability progression in the subject; (e) reduced number of new or newly enlarging T2 lesions in the subject; (f) reduced number of new non-enhancing Tl hypointense lesions in the subject; and (g) reduced number of Gd+ lesions in the subject; wherein the changes (a)-(g) are relative to a subject treated with placebo.
- a fumarate e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereof
- the subject has multiple sclerosis, such as relapsing-remitting multiple sclerosis, and is administered about 480 mg per day of a fumarate (e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereof) for a period of time sufficient to achieve one or more of changes (a)-(e) and (g) listed above.
- a fumarate e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereof
- the subject administered the fumarate has not received any multiple sclerosis treatment before being treated with fumarate.
- a subject having relapsing-remitting multiple sclerosis is administered about 480 mg per day of a fumarate (e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereof) for a period of time sufficient to achieve one or more of the following changes: (a) reduced annualized relapse rate of at least 30%; (b) reduced risk of disability progression of at least 30%>; and (c) reduced number of new or newly enlarging T2 lesions of at least 65 % in the subject, wherein the changes (a)-(c) are relative to a subject treated with placebo.
- a fumarate e.g., dimethyl fumarate, monomethyl fumarate, or a combination thereof
- a subject having relapsing-remitting multiple sclerosis is administered about 720 mg of a fumarate (e.g., dimethyl fumarate, monomethyl fumarate, or combinations thereof) per day for at least 24 weeks.
- a subject having multiple sclerosis is administered about 480 mg per day of a fumarate (e.g., dimethyl fumarate, monomethyl fumarate, or combinations thereof) for a period of time sufficient to preserve and/or increase myelin content in the subject.
- a subject younger than 40 years of age having multiple sclerosis is administered about 480 mg per day of a fumarate (e.g., dimethyl fumarate, monomethyl fumarate, or combinations thereof) for a period of time sufficient to achieve one or more of the following changes: (a) reduced frequency of relapse in the subject; (b) reduced probability of relapse in the subject; (c) reduced annualized relapse rate in the subject; (d) reduced risk of disability progression in the subject; (e) reduced number of new or newly enlarging T2 lesions in the subject; (f) reduced number of new non-enhancing Tl hypointense lesions in the subject; and (g) reduced number of Gd+ lesions in the subject; wherein the changes (a)-(g) are relative to a subject treated with placebo.
- a fumarate e.g., dimethyl fumarate, monomethyl fumarate, or combinations thereof
- Fig. 1 reports the proportion of subjects relapsed to a pre-specified primary endpoints after a 96 week period in a first Phase 3 clinical trial in which subjects with relapsing- remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, or dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose.
- BG-12 dimethyl fumarate
- TID dimethyl fumarate
- Fig. 2 reports a distribution of relapses of subjects over a 2 year time period in a first
- Phase 3 clinical trial in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, or dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose.
- BID dimethyl fumarate
- TID dimethyl fumarate
- Fig. 3 reports a risk of relapse after a 60 week period in a first Phase 3 clinical trial in which subjects with relapsing-remitting multiple sclerosis were administered a placebo or dimethyl fumarate (BG-12).
- Fig. 4 reports a progression of disability after a 96 week period in a first Phase 3 clinical trial in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12)) twice daily (BID) at 240 mg per dose, or dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose.
- BG-12 dimethyl fumarate
- TID dimethyl fumarate
- Fig. 5 reports a distribution of new or newly enlarging T2 lesions after a 2 year time period in a first Phase 3 clinical trial in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, or dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose.
- BG-12 dimethyl fumarate
- TID dimethyl fumarate
- Fig. 6 reports a distribution of new Gd+ lesions observed in subjects in a first Phase 3 clinical trial conducted over a 2 year time period in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, or dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose.
- BG-12 dimethyl fumarate
- TID dimethyl fumarate
- Fig. 7 depicts a mean change in magnetization transfer ratio ("MTR") from baseline in whole brain (“WB”) observed in subjects in a first Phase 3 clinical trial conducted over a 2 year time period in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, or dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose.
- MTR magnetization transfer ratio
- Fig. 8 depicts a mean change in magnetization transfer ratio ("MTR") from baseline in normal appearing brain tissue ("NABT”) observed in subjects in a first Phase 3 clinical trial conducted over a 2 year time period in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, or dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose.
- MTR magnetization transfer ratio
- Fig. 9 reports an annualized relapse rate observed in subjects in a second Phase 3 clinical trial conducted over a 2 year time period in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- BID dimethyl fumarate
- TID dimethyl fumarate
- Fig. 10 reports a distribution of relapses observed in subjects in a second Phase 3 clinical trial conducted over a 2 year time period in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- BID dimethyl fumarate
- TID dimethyl fumarate
- Fig. 11 reports the proportion of subjects relapsed to a pre-specified primary endpoints after a 96 week period in a second Phase 3 clinical trial in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG- 12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- BID dimethyl fumarate
- BG-12 dimethyl fumarate
- TID dimethyl fumarate
- Fig. 12 reports the time to 12-week confirmed disability progression in a second Phase 3 clinical trial in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- BID dimethyl fumarate
- TID dimethyl fumarate
- Fig. 13A reports a distribution of new or newly enlarging T2 lesions after a 2 year time period in a second Phase 3 clinical trial in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- BID dimethyl fumarate
- TID dimethyl fumarate
- Fig. 13B a distribution of new Tl hypointense lesions after a 2 year time period in a second Phase 3 clinical trial in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- BID dimethyl fumarate
- TID dimethyl fumarate
- Fig. 14 reports a mean number of Gd+ lesions observed in subjects in a second Phase 3 clinical trial conducted over a 2 year time period in which subjects with relapsing-remitting multiple sclerosis were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- BID dimethyl fumarate
- TID dimethyl fumarate
- Fig. 15A reports the median percent change from baseline in T2 hyperintense lesion volume observed after 1 year in subjects of a second Phase 3 clinical trial in which the subjects were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- Fig. 15B reports the median percent change from baseline in T2 hyperintense lesion volume observed after 2 years in subjects of a second Phase 3 clinical trial in which the subjects were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- Fig. 16A reports the median percent change from baseline in Tl hypointense lesion volume observed after 1 year in subjects of a second Phase 3 clinical trial in which the subjects were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- BG-12 dimethyl fumarate
- TID dimethyl fumarate
- 16B reports the median percent change from baseline in Tl hypointense lesion volume observed after 2 years in subjects of a second Phase 3 clinical trial in which the subjects were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- Fig. 17 reports the mean Gd + lesion volume observed in subjects after 2 years in subjects of a second Phase 3 clinical trial in which the subjects were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG- 12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- BG-12 dimethyl fumarate
- BID dimethyl fumarate
- TID dimethyl fumarate
- Fig. 18A reports the median percent change from baseline in whole brain volume observed after 2 years in subjects of a second Phase 3 clinical trial in which the subjects were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- Fig. 18B reports the median percent change from baseline in whole brain volume observed between week 24 and year 2 of a second Phase 3 clinical trial in which subjects were administered a placebo, dimethyl fumarate (BG-12) twice daily (BID) at 240 mg per dose, dimethyl fumarate (BG-12) three times daily (TID) at 240 mg per dose, or 20 mg glatiramer acetate once daily.
- treating refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disorder or to prevent progression of a disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art.
- An effective amount, manner, or mode can vary depending on the subject and may be tailored to the subject.
- the treatments offered by the methods disclosed herein aim at improving the conditions (or lessening the detrimental effects) of the disorders and not necessarily at completely eliminating or curing the disorders.
- Placebo refers to a composition without active agent (e.g., dimethyl fumarate, monomethyl fumarate, or combinations thereof). Placebo compositions can be prepared by known methods, including those described herein.
- EDSS refers to an Expanded Disability Status Scale.
- the EDSS scale runs from 0 to 10 and is:
- MS Multiple sclerosis
- CNS central nervous system
- MS is a chronic, progressing, disabling disease, which generally strikes its victims sometime 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 relapsing -remitting MS
- SP-MS secondary progressive MS
- PP-MS primary progressive MS
- PR-MS progressive relapsing MS
- Relapsing-remitting MS presents in the form of recurrent attacks of focal or multifocal neurologic dysfunction. Attacks may occur, remit, and recur, seemingly randomly over many years. Remission is often incomplete and as one attack follows another, a stepwise downward progression ensues with increasing permanent neurological deficit.
- the usual course of RR-MS is characterized by repeated relapses associated, for the majority of patients, with the eventual onset of disease progression. The subsequent course of the disease is unpredictable, although most patients with a relapsing-remitting disease will eventually develop secondary progressive disease.
- 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 demyelination also in the grey matter, particularly, in the cortex.
- Most current therapies for MS are aimed at the reduction of inflammation and suppression or modulation of the immune system.
- the available treatments for MS reduce inflammation and the number of new episodes but not all of the treatments have an effect on disease progression.
- Fumaric acid esters such as dimethyl fumarate (“DMF”)
- MS dimethyl fumarate
- DMF dimethyl fumarate
- DMF and monomethyl fumarate can exert neuroprotective effects such as reduction in demyelination and axonal damage in a mouse MS model with characteristic features of advanced stages of chronic forms of MS.
- MMF monomethyl fumarate
- a method of treating a subject with multiple sclerosis comprising administering to the subject a fumarate (e.g., DMF, MMF, or combinations thereof).
- a fumarate e.g., DMF, MMF, or combinations thereof.
- One embodiment includes reducing frequency of relapse in the subject; or reducing the cumulative probability of relapse in the subject; or reducing the annualized relapse rate in the subject; or reducing the risk of disability progression in the subject; or reducing the number of new or newly enlarging T2 lesions in the subject; or reduced number of new non-enhancing Tl hypointense lesions in the subject; or reducing the number of Gd+ lesions in the subject, wherein the reductions are relative to a subject treated with placebo comprising administering to the subject a fumarate (e.g., DMF, MMF, or combinations thereof).
- a fumarate e.g., DMF, MMF, or combinations thereof.
- the subject being treated with the fumarate e.g., DMF, MMF, or combinations thereof
- the subject being treated with the fumarate is less than 40 years of age.
- Also provided is a method of preserving and/or increasing myelin content in a subject having multiple sclerosis comprising administering about 480 mg per day of a fumarate (e.g., DMF, MMF, or combinations thereof) to the subject for a period of time sufficient to preserve and/or increase the myelin content.
- a fumarate e.g., DMF, MMF, or combinations thereof
- Preserving and/or increasing the myelin content means the content level of myelin in a group of subjects treated with fumarates (e.g., DMF, MMF, or a combination thereof) is on average higher that the content level of myelin in a placebo group of subjects.
- Fumarates e.g., DMF
- DMF can reduce the rate of loss of myelin in a subject and/or lead to myelin regeneration. Either mechanism can lead to the results observed in Example 5.
- the myelin content of a group of subjects treated with DMF is preserved and/or increased relative to that of a group of subjects receiving placebo with a mean improvement of 0.5% and can be as much as about 1%, based on whole brain magnetization transfer ratio (MTR), after a prolonged period of treatment (e.g., 1 year, 2 years, 5 years, or longer).
- MTR whole brain magnetization transfer ratio
- the fumarate can be, for example, a compound that converts to methyl hydrogen fumarate in vivo after administration. In one embodiment, only some of the fumarate present in a pharmaceutical composition is converted to methyl hydrogen fumarate in vivo. In one embodiment, the fumarate is dimethyl fumarate, monomethyl fumarate, fumaric acid, a salt of monomethyl fumarate, a salt of fumaric acid, or any combination thereof. In another embodiment, the fumarate can be a compound of formula (I): wherein Ri and R 2 are independently OH, O " , Ci-C 6 alkoxy, or a pharmaceutically acceptable salt thereof.
- the Ci-C 6 alkoxy can be chosen from, for example, C 1 -C5 alkoxy, C 1 -C4 alkoxy, C 1 -C3 alkoxy, Ci-C 2 alkoxy, C 2 -C 3 alkoxy, C 2 -C 4 alkoxy, C 2 -C 5 alkoxy, or C 2 -C 6 alkoxy and may be linear or branched.
- the fumarate is a dialkyl fumarate.
- the methods described above comprise administering DMF.
- DMF has the structure:
- the pharmaceutically acceptable salt can be a salt of a metal cation.
- the metal in the metal cation can be an alkali, alkaline earth, or transition metal such as Li, Na, K, Ca, Zn, Sr, Mg, Fe, or Mn.
- any of the methods described above includes treating a subject with a fumarate (e.g., DMF, MMF, or combinations thereof).
- the fumarate e.g., DMF, MMF, or combinations thereof
- the fumarate can be administered in an amount ranging 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).
- the amount of fumarate (e.g., DMF, MMF, or combinations thereof) administered will also 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.
- a fumarate e.g., DMF, MMF, or combinations thereof
- a subject for example orally, in an amount of from about 0.1 g to about 1 g per day, or for example, in an amount of from about 100 mg to about 800 mg per day.
- the fumarate e.g., DMF, MMF, or combinations thereof
- 720 mg of fumarate (e.g., DMF, MMF, or combinations thereof) per day may be administered in separate administrations of 2, 3, 4, 5 or 6 equal doses.
- 480 mg of fumarate (e.g., DMF, MMF, or combinations thereof) per day may be administered as a single daily dose of 480 mg or as 2 daily dosages of 240 mg each. If the 480 mg of fumarate (e.g., DMF, MMF, or combinations thereof) is administered in 2 daily doses, each dose can consist of 2 tablets containing 120 mg of the fumarate for a total dose of 240 mg of the fumarate.
- the time interval between administration of the first dose and the second dose can be, for example, about 8 hours apart, about 9 hours apart, about 10 hours apart, about 11 hours apart, or about 12 hours apart.
- the fumarate (e.g., DMF, MMF, or combinations thereof) can be administered, for example, once daily in an amount of about 480 mg.
- the fumarate e.g., DMF, MMF, or combinations thereof
- the fumarate (e.g., DMF, MMF, or combinations thereof) can be daily administered in an amount ranging from about 400 mg to about 600 mg, about 410 mg to about 590 mg, about 420 mg to about 580 mg, about 430 mg to about 570 mg, about 440 mg to about 560 mg, about 450 mg to about 550 mg, about 460 mg to about 540 mg, about 470 mg to about 530 mg, about 480 mg to about 520 mg, or about 490 mg to about 510 mg.
- the fumarate (e.g., DMF, MMF, or combinations thereof) can be administered daily in an amount ranging from about 432 mg to about 528 mg.
- the fumarate (e.g., DMF, MMF, or combinations thereof) dose can be, for example: 470 mg, 471 mg, 472 mg, 473 mg, 474 mg, 475 mg, 476 mg, 477 mg, 478 mg, 479 mg, 480 mg, 481 mg, 482 mg, 483 mg, 484 mg, 485 mg, 486 mg, 487 mg, 488 mg, 489 mg, or 490 mg.
- the fumarate (e.g., DMF, MMF, or combinations thereof) can be administered in the form of a sustained or controlled release pharmaceutical formulation.
- a sustained or controlled release pharmaceutical formulation can be prepared by various technologies by a skilled person in the art.
- the formulation can contain the fumarate (e.g., DMF, MMF, or combinations thereof), 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(ethylene)oxide, alkyl cellulose (e.g., ethyl cellulose and methyl cellulose), carboxymethyl cellulose, hydrophilic cellulose derivatives, and polyethylene glycol.
- Compositions are described in WO 2006/037342.
- the fumarate (e.g. DMF, MMF, or combinations thereof) can be administered by any method that permits the delivery of the fumarate (e.g., DMF, MMF, or combinations thereof) for treatment of multiple sclerosis, such as RR-MS.
- the fumarate e.g., DMF, MMF, or combinations thereof
- the fumarate can be administered via pills, tablets, microtablets, pellets, micropellets, capsules (e.g., containing microtablets), suppositories, liquid formulations for oral administration, in the form of dietary supplements, nutritional supplements, or a food.
- compositions can include well-known pharmaceutically acceptable excipients, e.g., if the composition is an aqueous solution containing the active agent, it can be an isotonic saline, 5% glucose, or others. Solubilizing agents such as cyclodextrins, or other solubilizing agents well known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compound. See, e.g., U.S. Pat. Nos. 6,509,376 and 6,436,992 for some formulations containing DMF or MMF.
- compositions can be administered orally, intranasally, transdermally, subcutaneously, intradermally, vaginally, intraaurally, intraocularly, intramuscularly, buccally, rectally, transmucosally, via inhalation, or intravenous administration.
- the fumarate e.g., DMF, MMF, or combinations thereof
- the time period for which the subject is dosed with the fumarate (e.g., DMF, MMF, or combinations thereof) in any of the methods described above can range, for example, from about 1 week to the remaining lifespan of the subject.
- the fumarate (e.g., DMF, MMF, or combinations thereof) and its composition can be dosed, for example, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 20 weeks, at least 30 weeks, at least 40 weeks, at least 50 weeks, at least 1 year, at least 60 weeks, at least 70 weeks, at least 80 weeks, at least 90 weeks, at least 100 weeks, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 6 years, at least 7 years, at least 8 years, at least 9 years, at least 10 years, at least 20 years, at least 30 years, at least 40 years, at least 50 years,
- the fumarate (e.g., DMF, MMF, or combinations thereof) and its composition can be dosed, for example, for a period of time ranging from about 1 week to about 100 years, about 1 week to about 90 years, about 1 week to about 80 years, about 1 week to about 70 years, about 1 week to about 60 years, about 1 week to about 50 years, about 1 week to about 40 years, about 1 week to about 30 years, about 1 week to about 20 years, about 1 week to about 10 years, about 1 week to about 9 years, about 1 week to about 8 years, about 1 week to about 7 years, about 1 week to about 6 years, about 1 week to about 5 years, about 1 week to about 4 years, about 1 week to about 3 years, about 1 week to about 2 years, about 1 week to about 100 weeks, about 1 week to about 1 year, about 1 week to about 50 weeks, about 1 week to about 40 weeks, about 1 week to about 30 weeks, about 1 week to about 20 weeks, about 1 week to about 10 weeks, or about 1 week to about 5 weeks.
- the fumarate (e.g., DMF, MMF, or combinations thereof) and its composition can be dosed, for example, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 20 weeks, about 30 weeks, about 40 weeks, about 50 weeks, about 1 year, about 60 weeks, about 70 weeks, about 80 weeks, about 90 weeks, about 100 weeks, about 2 years, about 3 years, about 4 years, about 5 years, about 6 years, about 7 years, about 8 years, about 9 years, about 10 years, about 20 years, about 30 years, about 40 years, about 50 years, about 60 years, about 70 years, about 80 years, about 90 years, or about 100 years.
- administering results in reducing the frequency of relapse in the subject relative to subject or group of subjects treated with placebo.
- Reduction in the frequency of relapse means that the number of relapses in a treated subject or a group of treated subjects are decreased relative to the number of relapses in a subject or a group of subjects treated with placebo. For example, a 50% reduction in frequency of relapse means that the group of treated subjects had on average 50%> fewer relapses than the placebo group.
- the reduction of the frequency of relapse in a subject or a group of treated subjects can range, for example, from about 10% to about 90% after at least 1 year of treatment. In one embodiment, the frequency of relapse in a subject or a group of treated subjects can range, for example, from about 10% to about 90% after at least 2 years of treatment.
- the frequency of relapse can be reduced, for example, from a range of about 10%> to 100%o after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the frequency of relapse can be reduced, for example, at least 15%>, at least 20%>, at least 25%>, at least 30%>, at least 35%>, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%o, at least 80%>, at least 85%>, at least 90%>, or at least 95%> after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- any time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the frequency of relapse can be reduced, for example from about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 20% to about 70%, or about 25% to about 65%> after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the reduction of the frequency of relapse in a subject or a group of subjects treated with fumarate can be, for example, from about 10% to about 90% after at least 1 year of treatment.
- the reduction in the proportion of subjects or group of subjects treated with fumarate (e.g., DMF, MMF, or combinations thereof) relapsing is, for example, from about 10% to about 90% after at least 2 years of treatment.
- relapsing is, for example, from a range of about 10%) to 90%) after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the reduction in the proportion of subjects or group of subjects treated with fumarate (e.g., DMF, MMF, or combinations thereof) relapsing is, for example, at least 30% at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%), or at least 80%> after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- any time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the reduction in the proportion of subjects or group of subjects treated with fumarate for example from about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 20% to about 80%, about 30% to about 80%, or about 40%) to about 80%> after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment)
- any time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment
- administration of the fumarate (e.g., DMF, MMF, or combinations thereof) or its composition in any of the described methods results in reducing the probability of relapse in a treated subject or a group of treated subjects relative to a subject or group of subjects treated with placebo.
- the fumarate e.g., DMF, MMF, or combinations thereof
- Reduction in the probability of relapse is the difference, at the same time point, between the probability of relapse of a subject or a group of subjects treated with placebo and the probability of relapse in a treated subject or a group of treated subjects.
- Probability data can be obtained from Kaplan-Meier plots of probability of relapse that have cumulative probability of relapse on the plot ordinate and time on the plot abscissa.
- Reduction in the probability of relapse in the subject or group of subjects can, for example, be: at least 0.005 after any time period of treatment, at least 0.01 after any time period of treatment, at least 0.1 at any time period of treatment, at least 0.05 after at least 12 weeks of treatment, at least 0.06 after at least 24 weeks of treatment, at least 0.14 after at least 36 weeks of treatment, at least 0.20 after at least 48 weeks of treatment, or at least 0.30 after at least 60 weeks of treatment.
- Reduction in the probability of relapse can be, for example, at least 0.005, at least 0.01, at least 0.05, at least 0.1, at least 0.15, at least 0.2, at least 0.25, at least 0.3, at least 0.35, at least 0.4, at least 0.45, at least 0.5, or at least 0.55, after any time period of treatment (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of treatment e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the probability of relapse can be about 0.01 to about 0.90, about 0.01 to about 0.80, about 0.01 to about 0.70, about 0.01 to about 0.60, about 0.01 to about 0.50, about 0.01 to about 0.40, about 0.10 to about to about 0.30, about 0.01 to about 0.20, or about 0.01 to about 0.10 after any time period of treatment (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- the reduction in probability of relapse in any subject or group of subjects described above after 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment is at least 0.005.
- administration of the fumarate (e.g., DMF, MMF, or combinations thereof) or its composition in any method described above results in reducing the annualized relapse rate in a treated subject or group of treated subjects relative to a subject or group of subjects treated with placebo.
- the annualized relapse rate in the subject or group of subjects can be reduced by, for example: at least 30%, about 30%> to about 70%>, about 50%>, at least 50%>, about 45%o to about 55%>, about 53%>, about 48%>, about 30%> after any time period of treatment e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- the reduction in annualized relapse rate can range from about 1% to 100%.
- the reduction in annualized relapse rate can be at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%), or at least 95% after any time period of treatment (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of treatment e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or
- the reduction in annualized relapse rate in any subject or group of subjects described above can be, for example, about 1% to about 90%>, about 1% to about 80%, about 1% to about 70%), about 1% to about 60%, about 1% to about 50%, about 1% to about 40%, about 1% to about 30%, about 1% to about 20%, about 1% to about 10%, about 10% to about 80%, about 10% to about 70%, about 20% to about 70%, about 25% to about 75%, about 20% to about 80%, about 30% to about 70%, about 30% to about 80%, about 35% to about 65%, about 40% to about 60%, or about 45% to about 55% after any time period of treatment (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of treatment e.g., at least 5, 12, 24, 36, 48, 60,
- the reduction in annualized relapse rate in any subject or group of subjects described above can, for example, change from about 25% after being treated for about 24 weeks to about 50% after being treated for about 2 years.
- the reduction in annualized relapse rate in any subject or group of subjects described above can, for example, change from about 30% after being treated for about 24 weeks to about 45% after being treated for about 2 years or about 40% after being treated for about 24 weeks to about 50% after being treated for about 2 years.
- the subject or group of subjects is administered 480 mg or 720 mg fumarate (e.g., DMF, MMF, or combinations thereof) per day.
- the reduction in annualized relapse rate in the subject or group of subjects decreases about 10% every 2 years over a treatment period of about 4 years. In one embodiment, the reduction in annualized relapse rate in the subject or group of subjects decreases about 10% every 2 years over a treatment period of about 4 years when the subject is administered about 480 mg of a fumarate daily (e.g., DMF, MMF, or combinations thereof daily).
- a fumarate daily e.g., DMF, MMF, or combinations thereof daily.
- administering results in reduction of the risk of disability progression in a treated subject or group of treated subjects relative to a subject or group of subjects treated with placebo.
- Disability progression is measured by EDSS.
- the risk of disability progression in any subject or group of subjects described above can be reduced by, for example: about 30% to about 40% at about 100 weeks of treatment, about 31% to about 37% at about 50 weeks of treatment, about 30% to about 40% at about 50 weeks of treatment, or about 31% to about 37% at about 100 weeks of treatment.
- the risk of disability progression in any subject or group of subjects described above can be reduced from about 1% to 100% after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the risk of disability progression can be reduced by at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%o, at least 90%>, or at least 95% after any time period of treatment (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of treatment e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48
- the risk of disability progression can be reduced, for example, from about 1% to about 90%, about 1% to about 80%, about 1% to about 70%, about 1% to about 60%, about 1% to about 50%, about 1% to about 40%, about 1% to about 30%, about 1% to about 20%, about 1% to about 10%, about 20% to about 70%, about 25% to about 65%, about 30% to about 60%), about 35% to about 55%, or about 40% to about 50% after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of
- administration of the fumarate (e.g., DMF, MMF, or combinations thereof) or its composition in any of the methods described above results in reduction of the number of new or newly enlarging T2 lesions in a treated subject or group of treated subjects relative to a subject or group of treated subjects treated with placebo.
- the reduction can be ascertained by routine magnetic resonance imaging ("MRI") methods.
- MRI magnetic resonance imaging
- the number of new or newly enlarging T2 lesions in any subject or group of subjects described above can be reduced by, for example: about 70% to about 90% after at least 100 weeks of treatment, at least 85% after at least 100 weeks of treatment, or at least 74% after at least 100 weeks of treatment.
- the reduction in the number of new or newly enlarging T2 lesions in any subject or group of subjects described above can range from about 1% to 100% after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the reduction in the number of new or newly enlarging T2 lesions can be at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10,
- the reduction in the number of new or newly enlarging T2 lesions in any subject or group of subjects described above can range, for example, from about 1%> to about 90%>, about 1%) to about 80%>, about 1%> to about 70%>, about 1%> to about 60%>, about 1%> to about 50%, about 1% to about 40%, about 1 % to about 30%, about 1% to about 20%, about 1 % to about 10%, about 30% to about 99%, about 35% to about 99%, about 40% to about 99%, about 45% to about 99%, about 50% to about 99%, about 30% to about 95%, about 35% to about 95%, about 40% to about 95%, about 45% to about 95%, about 50% to about 95%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 30% to about 85%, about 35% to about 85%, about 40% to about 85%, about 45% to about 85%, about 50% to about 85%, about 30% to
- administration of the fumarate (e.g., DMF, MMF, or combinations thereof) or its composition in any of the methods described above results in reduction of the number of new non-enhancing Tl hypointense lesions in a treated subject or group of treated subjects relative to a subject or group of subjects treated with placebo.
- the reduction can be ascertained by routine magnetic resonance imaging ("MRI") methods.
- MRI magnetic resonance imaging
- the reduction of the number of new non-enhancing Tl hypointense lesions in any subject or group of subjects described above can be determined after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the reduction of the number of new non-enhancing Tl hypointense lesions in any subject or group of subjects described above can range, for example, from about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 30% to about 85%, about 35% to about 85%, about 40% to about 85%, about 45% to about 85%, about 50% to about 85%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, or about 50% to about 80%) after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years
- the number of new non-enhancing Tl hypointense lesions in any subject or group of subjects described above can be reduced by, for example, about 50%> to about 70% after at least 48 weeks of treatment. In another embodiment, the number of new non-enhancing Tl hypointense lesions in any subject or group of subjects described above can be reduced by, for example, at least 60% after at least 96 weeks of treatment. In yet another embodiment, the number of new non-enhancing Tl hypointense lesions in any subject or group of subjects described above can be reduced by, for example, about 55% to about 65% after at least 48 weeks of treatment. In still yet another embodiment, the number of new non-enhancing Tl hypointense lesions in any subject or group of subjects described above can be reduced by, for example, about 60%> to about 70%> after at least 96 weeks of treatment.
- administration of the fumarate (e.g., DMF, MMF, or combinations thereof) or its composition in any of the above described methods results in reduction in the number of Gd+ lesions in the treated subject or group of treated subjects relative to a subject or group of treated subjects treated with placebo.
- the reduction in the number of Gd+ lesions in any subject or group of subjects described above can be determined after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- the percentage reduction of the number of Gd+ lesions in any subject or group of subjects described above can range, for example, from about 10% to 100% after, for example, at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- the percentage reduction in the number of Gd+ lesions in any subject or group of subjects described above can range, for example, from about 10%>, to about 98%>, about 10%> to about 97%, about 10% to about 96%, about 10% to about 95%, about 10% to about 94%, about 10% to about 93%, about 10% to about 92%, about 10% to about 91%, about 10% to about 90%, about 10% to about 85%, about 10% to about 80%, about 10% to about 75%, about 10% to about 70%, about 15% to about 99%, about 20% to about 99%, about 25% to about 99%, about 30% to about 99%, about 35% to about 99%, about 40% to about 99%, about 45% to about 99%, about 50% to about 99%, about 55% to about 99%, about 60% to about 99%, about 65% to about 99%, or about 70% to about 99%, about 30% to about 95%, about 35% to about 95%, about 40% to about 95%, about 45% to about 95%, about 50% to about 95%, about 30% to about 90%, about
- the percentage reduction in the number of Gd+ lesions in any subject or group of subjects described above can be, for example, at least 5%>, at least 10%>, at least 15%>, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1 , 2, 3, 4, 5, 10, 15, or 20 years
- the percentage reduction in the number of Gd+ lesion in any subject or group of subjects described above can be, for example, about 20%>, about 25%>, about 30%>, about 35%>, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%), about 80%), or about 90%> after any time period of administration (e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment).
- time period of administration e.g., at least 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment or about 5, 12, 24, 36, 48, 60, 96, or 100 weeks or 1, 2, 3, 4, 5, 10, 15, or 20 years of treatment.
- R -MS relapsing-remitting multiple sclerosis
- Subjects 18-55 years of age with McDonald criteria diagnosis of RR-MS and an Expanded Disability Status Scale score of 0.0-5.0 (inclusive) were eligible for enrolment.
- Subjects were randomly assigned in a 1 : 1 : 1 ratio to placebo, dimethyl fumarate 240 mg PO twice daily (BID), or dimethyl fumarate three times daily (TID).
- Safety and tolerability were assessed by continuous adverse event ("AE") monitoring and laboratory tests at all monthly visits. Additionally, physical examination, vital signs, and 12-lead ECG were evaluated. As an ethical consideration, subjects' reconsent was required following any protocol-defined disability progression or relapse.
- AEs were reported by 95%, 96%, and 95%, of subjects receiving placebo, dimethyl fumarate BID, and dimethyl fumarate TID, respectively. AEs resulted in 55 (13%)), 65 (16%)), and 68 (16%) subjects discontinuing treatment in the placebo, dimethyl fumarate BID, and dimethyl fumarate TID arms, respectively. The most frequently reported AEs were flushing, MS relapse, nasopharyngitis, headache, diarrhea, and fatigue.
- Example 1 The primary endpoint of the study in Example 1 was the proportion of subjects relapsing at 2 years, with relapses confirmed by an independent neurology evaluation committee ("INEC”) to ensure consistent and accurate reporting across sites. Secondary clinical efficacy endpoints at 2 years were the annualized relapse rate (“ARR”) and disability progression using EDSS. Efficacy analyses were conducted on the intention-to-treat population.
- Dimethyl fumarate BID and TID reduced the proportion of subjects relapsing by 49% and 50%>, respectively, compared with placebo (P ⁇ 0.0001) at 2 years.
- ARR was 0.36 with placebo, and 0.17 and 0.19 with dimethyl fumarate BID and TID, corresponding to reductions of 53% and 48% for dimethyl fumarate BID and TID (P ⁇ 0.001).
- the risk of confirmed, 12-week disability progression was reduced by 38% with dimethyl fumarate BID (P ⁇ 0.01) and approximately 34% with dimethyl fumarate TID (P ⁇ 0.05).
- the overall incidence of adverse and serious adverse events was similar among the placebo and both dimethyl fumarate treatment groups.
- Subjects from 76 sites out of 198 participating in the study described in Example 1 had MRI scans at baseline, 24 weeks, 1 year and 2 years. Number of new or newly enlarging T2 lesions and number of gadolinium-enhancing (Gd+) lesions at 2 years were secondary endpoints of the study. Analyses were conducted on the MRI intention-to-treat population.
- the mean number of new or newly enlarging T2 lesions was reduced by 85% and 74% in the dimethyl fumarate BID and TID groups, respectively (P ⁇ 0.001 for both) and the mean number of Gd+ lesions was reduced by 94% and 72%, respectively (P ⁇ 0.001 for both) in the BID and TID groups, compared with placebo.
- Subjects participating in the study described in Example 1 were provided an SF-36 questionnaire to measure the subjects' health status and health-related quality of life (“QoL”) at baseline, 6, 12, and 24 months, on eight multi-item, 100-point scales, with higher scores indicating higher QoL. These scores were used to calculate the Physical Component Summary (“PCS”) and Mental Component Summary (“MCS”) scores. In addition, the subjects' global impression of well-being was assessed at baseline and every 3 months using a 100-point, visual analogue scale (VAS) with higher score indicating improvement in well- being.
- PCS Physical Component Summary
- MCS Mental Component Summary
- dimethyl fumarate significantly improved physical functioning and general well-being in subjects with RR-MS.
- Dimethyl fumarate benefits on relapse rate and EDSS progression in the study described in Example 1 are reflected in subject-reported, health-related quality of life, further supporting its role as an effective oral treatment option for subjects with RR-MS.
- Example 5
- Example 1 The study described in Example 1 included a substudy to examine change in magnetization transfer ratio ("MTR") with treatment.
- MTR imaging has been proposed for use as a biomarker of changes in the myelin content of brain white matter.
- the aim of the study was to determine change in brain and lesion MTR in RR-MS.
- MTR scans were obtained in a subset of subjects at baseline and 6, 12 and 24 months, using manufacturer- supplied MT pulse sequences.
- MTR substudies were implemented at 64 of 76 MRI sites (84%) and included a total of 540 subjects: 176 in the dimethyl fumarate 240 mg bid group, 184 in the dimethyl fumarate 240 mg tid group, and 180 in the placebo group.
- dimethyl fumarate 240 mg bid and tid groups larger increases from baseline were observed in whole brain MTR (0.129%) and 0.096%>), respectively) and normal appearing brain tissue MTR (0.190%), 0.115%), respectively) compared with placebo (-0.386%> and -0.392%> for whole brain and normal appearing brain MTRs, respectively).
- dimethyl fumarate 240 mg BID and dimethyl fumarate 240 mg BID were more efficacious in subjects under 40 years of age than subjects that were 40 years or older.
- BID dimethyl fumarate 240 mg PO twice daily
- TID dimethyl fumarate three times daily
- QD glatiramer acetate 20 mg SC once daily
- AEs were reported by 92%>, 94%>, 92%>, and 87% of subjects receiving placebo, dimethyl fumarate BID, dimethyl fumarate TID, and glatiramer acetate respectively. AEs resulted in 38 (10%), 44 (12%), 41 (12%), and 35 (10%) subjects discontinuing treatment in the placebo, dimethyl fumarate BID, dimethyl fumarate TID, and glatiramer acetate arms, respectively.
- the most frequently reported AEs associated with dimethyl fumarate were flushing, diarrhea, nausea, upper respiratory tract infection, abdominal pain, and proteinuria.
- the primary endpoint of the second phase 3 clinical trial was the annualized relapse rate over 2 years. Secondary endpoints of the second phase 3 clinical trial were the number of new or newly enlarging T2 hyperintense lesions at 2 years, proportion of patients relapsed at 2 years, disability progression as measured by EDSS, and number of new Tl hypointense lesions at 2 years.
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EP12789291.7A EP2713724A4 (en) | 2011-05-26 | 2012-05-25 | Methods of treating multiple sclerosis and preserving and/or increasing myelin content |
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BR112013030169A BR112013030169A2 (en) | 2011-05-26 | 2012-05-25 | Multiple sclerosis treatment methods and preservation and / or increase of myelin content |
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ZA2013/08681A ZA201308681B (en) | 2011-05-26 | 2013-11-19 | Methods of treating multipkle sclerosis and preserving and/or increasing myelin content |
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Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014031901A1 (en) * | 2012-08-22 | 2014-02-27 | Xenoport, Inc. | Methods of use for monomethyl fumarate and prodrugs thereof |
US8669281B1 (en) | 2013-03-14 | 2014-03-11 | Alkermes Pharma Ireland Limited | Prodrugs of fumarates and their use in treating various diseases |
CN103724198A (en) * | 2013-11-28 | 2014-04-16 | 镇江圣安医药有限公司 | Novel derivative of dimethyl fumarate and application of novel derivative |
US8980832B2 (en) | 2003-09-09 | 2015-03-17 | Biogen Idec International Gmbh | Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma |
US9302977B2 (en) | 2013-06-07 | 2016-04-05 | Xenoport, Inc. | Method of making monomethyl fumarate |
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US9326965B2 (en) | 2014-02-28 | 2016-05-03 | Banner Life Sciences Llc | Controlled release fumarate esters |
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US9421182B2 (en) | 2013-06-21 | 2016-08-23 | Xenoport, Inc. | Cocrystals of dimethyl fumarate |
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US9505776B2 (en) | 2013-03-14 | 2016-11-29 | Alkermes Pharma Ireland Limited | Prodrugs of fumarates and their use in treating various diseases |
US9566259B1 (en) | 2015-08-31 | 2017-02-14 | Banner Life Sciences Llc | Fumarate ester dosage forms |
US9597292B2 (en) | 2012-08-22 | 2017-03-21 | Xenoport, Inc. | Oral dosage forms of methyl hydrogen fumarate and prodrugs thereof |
US9604922B2 (en) | 2014-02-24 | 2017-03-28 | Alkermes Pharma Ireland Limited | Sulfonamide and sulfinamide prodrugs of fumarates and their use in treating various diseases |
US9999672B2 (en) | 2014-03-24 | 2018-06-19 | Xenoport, Inc. | Pharmaceutical compositions of fumaric acid esters |
US10098863B2 (en) | 2014-02-28 | 2018-10-16 | Banner Life Sciences Llc | Fumarate esters |
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US10245253B2 (en) | 2014-12-11 | 2019-04-02 | Actelion Pharmaceuticals Ltd | Pharmaceutical combination comprising a selective S1P1 receptor agonist |
US10399924B2 (en) | 2012-12-21 | 2019-09-03 | Biogen Ma Inc. | Deuterium substituted fumarate derivatives |
US10945984B2 (en) | 2012-08-22 | 2021-03-16 | Arbor Pharmaceuticals, Llc | Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects |
US10959972B2 (en) | 2014-11-17 | 2021-03-30 | Biogen Ma Inc. | Methods of treating multiple sclerosis |
US11052062B2 (en) | 2004-10-08 | 2021-07-06 | Biogen Swiss Manufacturing Gmbh | Controlled release pharmaceutical compositions comprising a fumaric acid ester |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RS56972B1 (en) | 2011-06-08 | 2018-05-31 | Biogen Ma Inc | Process for preparing high purity and crystalline dimethyl fumarate |
JP6564868B2 (en) * | 2014-10-27 | 2019-08-21 | セリックス バイオ プライヴェート リミテッドCellix Bio Private Limited | Three component salts of fumaric acid monomethyl ester and piperazine or ethylenediamine for the treatment of multiple sclerosis |
WO2021142062A1 (en) | 2020-01-10 | 2021-07-15 | Banner Life Sciences Llc | Fumarate ester dosage forms with enhanced gastrointestinal tolerability |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7320999B2 (en) * | 1998-11-19 | 2008-01-22 | Fumapharm Ag | Dimethyl fumarate for the treatment of multiple sclerosis |
US20080260728A1 (en) * | 2004-08-20 | 2008-10-23 | Biogen Idec Ma Inc. | Treatment of Severe Multiple Sclerosis |
US20080299196A1 (en) * | 2005-10-07 | 2008-12-04 | Aditech Pharma Ab | Controlled Release Pharmaceutical Compositions Comprising a Fumaric Acid Ester |
US20100048651A1 (en) * | 2008-08-19 | 2010-02-25 | Xenoport, Inc. | Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use |
US20100130607A1 (en) * | 2007-02-08 | 2010-05-27 | Ralf Gold | Neuroprotection in demyelinating diseases |
US20110112196A1 (en) * | 2007-02-08 | 2011-05-12 | Matvey E Lukashev | Nrf2 screening assays and related methods and compositions |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19721099C2 (en) * | 1997-05-20 | 1999-12-02 | Fumapharm Ag Muri | Use of fumaric acid derivatives |
CN101056624A (en) * | 2004-10-08 | 2007-10-17 | Adi技术制药股份公司 | Controlled release pharmaceutical compositions comprising a fumaric acid ester |
NZ595941A (en) * | 2009-04-29 | 2014-02-28 | Biogen Idec Inc | Treatment of neurodegeneration and neuroinflammation |
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7320999B2 (en) * | 1998-11-19 | 2008-01-22 | Fumapharm Ag | Dimethyl fumarate for the treatment of multiple sclerosis |
US20080260728A1 (en) * | 2004-08-20 | 2008-10-23 | Biogen Idec Ma Inc. | Treatment of Severe Multiple Sclerosis |
US20080299196A1 (en) * | 2005-10-07 | 2008-12-04 | Aditech Pharma Ab | Controlled Release Pharmaceutical Compositions Comprising a Fumaric Acid Ester |
US20100130607A1 (en) * | 2007-02-08 | 2010-05-27 | Ralf Gold | Neuroprotection in demyelinating diseases |
US20110112196A1 (en) * | 2007-02-08 | 2011-05-12 | Matvey E Lukashev | Nrf2 screening assays and related methods and compositions |
US20100048651A1 (en) * | 2008-08-19 | 2010-02-25 | Xenoport, Inc. | Prodrugs of methyl hydrogen fumarate, pharmaceutical compositions thereof, and methods of use |
Non-Patent Citations (4)
Title |
---|
FOX: "BG00012-A Novel Oral Therapy in Development for the Treatment of Multiple Sclerosis", EUROPEAN NEUROLOGICAL REVIEW, 2008, pages 99 - 103, XP008172592 * |
GOLD ET AL.: "Oral Therapies for Multiple Sclerosis: A Review of Agents in Phase III Development or Recently Approved", CNS DRUGS, vol. 25, no. 1, January 2011 (2011-01-01), pages 37 - 52, XP008139191 * |
KAPPOS ET AL.: "Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase llb study", THE LANCET, vol. 372, no. 9648, 2008, pages 1463 - 1472, XP025584415 * |
See also references of EP2713724A4 * |
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Also Published As
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CL2013003358A1 (en) | 2014-08-01 |
BR112013030169A2 (en) | 2016-08-09 |
IL229448A0 (en) | 2014-01-30 |
EA201391578A1 (en) | 2014-05-30 |
US20140163100A1 (en) | 2014-06-12 |
CN103732062A (en) | 2014-04-16 |
EP2713724A4 (en) | 2015-03-11 |
PE20141316A1 (en) | 2014-10-01 |
AU2012258558A1 (en) | 2013-05-02 |
MX2013013781A (en) | 2014-01-08 |
CA2836480A1 (en) | 2012-11-29 |
ZA201308681B (en) | 2017-11-29 |
SG195049A1 (en) | 2013-12-30 |
ECSP13013117A (en) | 2014-06-30 |
JP2014515373A (en) | 2014-06-30 |
CO6811862A2 (en) | 2013-12-16 |
KR20140036257A (en) | 2014-03-25 |
EP2713724A1 (en) | 2014-04-09 |
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