WO2004078145A2

WO2004078145A2 - Combination therapy with glatiramer acetate and simvastatin for the treatment of multiple sclerosis

Info

Publication number: WO2004078145A2
Application number: PCT/US2004/006806
Authority: WO
Inventors: Liat Hayardeny; Dina Kofler
Original assignee: Teva Pharmaceutical Industries, Ltd.; Teva Pharmaceuticals Usa, Inc.
Priority date: 2003-03-04
Filing date: 2004-03-04
Publication date: 2004-09-16
Also published as: WO2004078145A3; WO2004078145B1

Abstract

The subject invention provides a method of treating a subject afflicted with a form of multiple sclerosis comprising periodically administering to the subject an amount of glatiramer acetate and an amount of simvastatin, wherein the amounts when taken together are effective to alleviate a symptom of the form of multiple sclerosis in the subject so as to thereby treat the subject. The subject invention also provides a package comprising glatiramer acetate, simvastatin and instructions for use of the together to alleviate a symptom of a form of multiple sclerosis in a subject. Additionally, the subject invention provides a pharmaceutical composition comprising an amount of glatiramer acetate and an amount of simvastatin, wherein the amounts when taken together are effective to alleviate a symptom of a form of multiple sclerosis in a subject. The subject invention further provides a pharmaceutical combination comprising separate dosage forms of an amount of glatiramer acetate and an amount of simvastatin, which combination is useful to alleviate a symptom of a form of multiple sclerosis in a subject.

Description

Docket No. 68253-A-PCT/JP /GJG/DJK

COMBINATION THERAPY WITH GLATIRAMER ACETATE AND SIMVASTATIN FOR THE TREATMENT OF MULTIPLE SCLEROSIS

The present application claims the benefit of U.S. Provisional Application No. 60/451,817, filed March 4, 2003, which is incorporated by reference herein.

Throughout this application, various events are referenced in' parenthesis. Full citations for these publications may be found listed in alphabetical order at the end of the specification immediately preceding the claims . The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

Field of the Invention

The subject invention relates to^' combination therapy for treating multiple sclerosis.

Background of the Invention

One of the more common neurologic diseases in human adults is multiple sclerosis. This condition is a chronic, inflammatory CNS disease characterized pathologically by demyelination. There are five main forms of multiple sclerosis: 1) benign multiple sclerosis; 2) relapsing-remitting multiple sclerosis (RR-MS) ; 3) secondary progressive multiple sclerosis (SP-MS) ; 4) primary progressive multiple sclerosis (PP-MS) ; and 5) progressive-relapsing multiple sclerosis (PR-MS) . Benign multiple sclerosis is characterized by 1-2 exacerbations with complete recovery, no lasting disability and no disease progression for 10-15 years after the initial onset. Benign multiple sclerosis may, however, progress into other forms of multiple sclerosis. Patients suffering from RR-MS experience sporadic exacerbations or relapses, as well as periods of remission. Lesions and evidence of axonal loss may or may not be visible on MRI for patients with RR-MS. SP-MS may evolve from RR-MS. Patients afflicted with SP-MS have relapses, a diminishing degree of recovery during remissions, less frequent remissions and more pronounced neurological deficits than RR-MS patients. Enlarged ventricles, which are markers for atrophy of the corpus callosum, idline center and spinal cord, are visible on MRI of patients with SP-MS. PP-MS is characterized by a steady progression of increasing neurological deficits without distinct attacks or remissions. Cerebral lesions, diffuse spinal cord damage and evidence of axonal loss are evident on the MRI of patients with PP-MS. PR-MS has periods of acute pyjccrbationr. π'hAe proceeding along = course of increasin'σ neurological deficits without remissions . Lesions are evident on MRI of patients suffering from PR-MS (Multiple sclerosis: its diagnosis, symptoms, types and stages) .

Researchers have hypothesized that multiple sclerosis is an autoimmune disease (Compston; Hafler and einer; Olsson) . An autoimmune hypothesis is supported by the. experimental allergic encephalomyelitis (EAE) model of multiple sclerosis, where the injection of certain myelin components into genetically susceptible animals leads to T cell-mediated CNS demyelination (Parkman) . Another theory regarding the pathogenesis of multiple sclerosis is that a virus, bacteria or other agent, precipitates an inflammatory response in the CNS, which leads to either direct or indirect ("bystander") myelin destruction, potentially with an induced autoimmune component (Lampert; Martyn) . Another experimental model of multiple sclerosis, Theiler's murine encephalomyelitis virus (TMEV) (Dal Canto and Lipton; Rodriguez et al.), supports the theory that a foreign agent initiates multiple sclerosis. In the TMEV model, injection of the virus results in spinal cord demyelination.

Glatiramer acetate (GA) , also known as Copolymer-1, has been shown to be effective in treating multiple sclerosis (MS) (Lampert, P.W.). Daily subcutaneous injections of glatiramer acetate (20 mg/injection) reduce relapse rates, progression of disability, appearance of new lesions by magnetic resonance imaging (MRI), (Johnson, K.P. et al . ) and appearance of "black holes" (Filippi, M. et al . ) .

COPAXONE® is the brand name for a formulation containing glatiramer acetate as the active ingredient. Glatiramer acetate is approved for reducing the frequency of relapses in relapsing- remitting multiple sclerosis. Glatiramer acetate consists of the acetate salts of synthetic polypeptides containing four naturally occurring amino acids: L-glutamic acid, L-alan.ine. L- tyrosine, and L-lysine with an average molar fraction in

COPAXONE® of 0.141, 0.427, 0.095 and 0.338, respectively. In

COPAXONE®, the average molecular weight of the glatiramer acetate is 4,700-11,000 daltonε. Chemically, glatiramer acetate is designated L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine, acetate (salt). Its structural formula is:

(Glu, Ala, Lys, Tyr)_x-CH₃COOH

(C₅H₉N0₄-C₃H₇N0₂-C₆H₁₄N₂0₂-C₉H₁₁N0₃ ) _χ-χC₂H₄0₂

CAS - 147245-92-9.

The recommended dosing schedule of COPAXONE® for relapsing- remitting multiple sclerosis is 20 mg per day injected subcutaneously (Physician's Desk Reference, 2003; see also U.S. Patent Nos . 3,849,550; 5,800,808; 5,858,964, 5,981,589; 6,048,898; 6,054,430; 6,214,791; 6,342,476; and 6,362,161, all of which are hereby incorporated by reference) .

Simvastatin is commerically available under the tradename, ZOCOR®. Simvastatin is butanoic acid, 2 , 2-dimethyl- 1,2,3,7,8, 8a-hexahydro-3 , 7-dimethyl-8- [2 (tetrahydro-4-hydroxy-6- oxo-2H-pyran-2-yl) -ethyl] -1-naphthalenyl ester, [1S- [lα,3α,7β,8β(2S*,4S*) , -8aβ] ] . The empirical formula of simvastatin is C₂₅H₃₈0₅ and its molecular weight is 418.57. Its structural formula is:

The dosage range is 5-80 g/day. The recommended usual starting dose is 20 mg once a day in the evening. At intervals of 4 weeks or more, dosage should be adjusted according to the patient's response to therapy and established treatment guidelines (Physician's Desk Reference).

The administration of two drugs to treat a given condition, suet as a form of multiple sclerosis, raises a number of potential problems. In vivo interactions between two drugs are complex. The effects of any single drug are related to its absorption, distribution, and elimination. When two drugs are introduced into the body, each drug can affect the absorption, distribution, and elimination of the other and hence, alter he effects of the other. For instance, one drug may inhibit, activate or induce the production of enzymes involved in e metabolic route ol elimination of the other drug (-Guidance fo2 Industry. In vivo drug metabolism/drug interaction studies - study design, data analysis, and recommendations for dosi-ng an< labeling) . Thus, when two drugs are administered to tr-eat th* same condition, it is unpredictable whether each will comple ent, have no effect on, or interfere with, the therapeutic activity of the other in a human subject.

Not only may the interaction between two drugs affect the intended therapeutic activity of each drug, but the interaction may increase the levels of toxic metabolites (Guidance for Industry. In vivo drug metabolism/drug interaction studies - study design, data analysis, and recommendations for dosing and labeling) . The interaction may also heighten or lessen the side effects of each drug. Hence, upon administration of two drugs to treat a disease, it is unpredictable what change will occur in the negative side profile of each drug.

Additionally, it is accurately difficult to predict when the effects of the interaction between the two drugs will become manifest. For example, metabolic interactions between drugs may become apparent upon the initial administration of the second drug, after the two have reached a steady-state concentration or upon discontinuation of one of the drugs (Guidance for Industry. In vivo drug metabolism/drug interaction studies - study design, data analysis, and recommendations for dosing; and labeling) .

Thus, the success of one drug or each drug alone, in an in vi tro model, an animal model, or in humans, may not correlate into efficacy when both drugs are administered to humans.

In accordance with the subject invention, .glatiramer acetate and simvastatin are effective in combination to treat a form of multiple sclerosis, specifically, relapsing-remitting multiple sclerosis. Summary of the Invention

The subject invention provides a method of treating a subject afflicted with a form of multiple sclerosis comprising periodically administering to the subject an amount of glatiramer acetate and an amount of simvastatin, wherein the amounts when taken together are effective to alleviate a symptom of the form of multiple sclerosis in the subject so as to thereby treat the subject.

In addition, the subject invention provides a package comprising i) a first pharmaceuti al composition comprising- «^•" amount of glatiramer acetate and a pharmaceutically acceptable carrier; ii) a second pharmaceutical composition comprising an amount of simvastatin and a pharmaceutically acceptable carrier; and iii) instructions for use of the first and second pharmaceutical compositions together to alleviate a symptom of a form of multiple sclerosis in a subject.

The subject invention further provides a pharmaceutical composition comprising an amount of glatiramer acetate and an amount of simvastatin, wherein the amounts when taken together are effective to alleviate a symptom of a form of multiple sclerosis in a subject.

πetailed Description of the Invention

In one embodiment, the form of multiple sclerosis is relapsing- reιAttiτισ multiple sclerosis.

In another embodiment, the subject is a human being.

In a further embodiment, each of the amount of glatiramer. acetate when taken alone, and the amount of simvastatin when taken alone is effective to alleviate the symptom of the form of multiple sclerosis.

In an embodiment, either the amount of glatiramer acetate when taken alone, the amount of simvastatin when taken alone or each such amount when taken alone is not effective to alleviate the symptom of the form of multiple sclerosis.

In yet another embodiment, the symptom is the frequency of relapses, the frequency of clinical exacerbation, or the accumulation of physical disability.

In one embodiment, the amount of glatiramer acetate may be IC to 80 mg; or 12 to 70 mg; or 14 to 60 g; or lb to 50 g; or l€ to 40 mg; or 20 to 30 mg; or 20 mg. For each amount of glatiramer acetate, the amount of simvastatin may be S-80 mg; oi

8-70 mg; or 10-60 g; or 12-50 mg; or 14-40 mg; or 1*6-30 mg; OΪ 18-25 mg; or 20 mg. Alternatively, the amount of glatiramer acetate may be in the range from 10 to 600 mg/week,- or 100 to 550 mg/week; or 150 to 500 mg/week; or 200 to 450 mg/week; or 250 to 400 mg/week; or 300 to 350 mg/week; or 300 mg/week.

In another embodiment, the amount of glatiramer acetate may be in the range from 50 to 150 mg/day; or 60 to 140 mg/day; or 70 to 130 mg/day; or 80 to 120 mg/day; or 90 to 110 mg/day; or 100 mg/day.

Alternatively, the amount of glatiramer acetate may be in the range from 10 to 80 mg/day; or 12 to 70 mg/day; or 4 to 60 mg/day; or 16 to 50 mg/day; or 18 to 40 mg/day; or 19 to 30 mg/day; or 20 mg/day.

In one embodiment, the periodic administration of glatiramer acetate is effected daily.

In another embodiment, the periodic administration of glatiramer acetate is effected twice daily at one half the amount.

In an additional embodiment, the periodic administration of glatiramer acetate is effected once every 3 to 11 days; or once every 5 to 9 days; or once every 7 days; or once every 24 hours.

For each administration schedule of glatiramer acetate, the simvastatin may be administered once every 6-30 hours; or once every 8-28 hours; or once every 10-26 hours; or once every 12-24 hours; or once every 12 hours; or once every 24 hours.

In an embodiment, the periodic administration of simvastatin iε effected in the evening.

In a further embodiment, the administration of the glatirame.: acetate substantially precedes the administration of th€ simvastatin.

In an added embodiment, the administration of the simvastatin substantially precedes the administration of the glatiramer acetate.

In one embodiment, the glatiramer acetate and the simvastatin- may be administered for a period of time of at least' 4 days. In a further embodiment, the period of time may be 5 days to 5 years; or 10 days to 3 years; or 2 weeks to 1 year; or 1 month to 6 months; or 3 months to 4 months. In yet another embodiment, the glatiramer acetate and the simvastatin may be administered for the lifetime of the subject.

The administration of simvastatin or glatiramer acetate may each independently be oral, nasal, pulmonary, parenteral, intravenous, intra-articular, tranεdermal, intradermal, subcutaneous, topical, intramuscular, rectal-, intrathecal, intraocular, buccal or by gavage. For simvastatin, the preferred route of administration is oral or by gavage. The preferred route of administration for glatiramer acetate is subcutaneous or oral. One of skill in the art would recognize that doses at the higher end of the range may be required for oral administration.

In one embodiment, the administration of the glatiramer acetate may be subcutaneous, intraperitoneal , intravenous, intramuscular, intraocular or oral and the administration of the simvastatin may be oral. In another embodiment, he. administration of the glatiramer acetate may be subcutaneous and the ad inis raticr. cf the simvastatin may be oral.

The subject invention also provides a package comprising i) a first pharmaceutical composition comprising an amount of glatiramer acetate and a pharmaceutically acceptable carrier; ii) a second pharmaceutical composition comprising an amount of simvastatin and a pharmaceutically acceptable carrier; and iii) instructions for use of the first and second pharmaceutical compositions together to alleviate a symptom of a form of multiple sclerosis in a subject.

In an embodiment of the package, the amount of glatiramer acetate may be in the range from 10 to 600 mg; or 100 to 550 mg; or 150 to 500 g; or 200 to 450 mg; or 250 to 400 mg; or 300 to 350 mg; or 300 mg.

In another embodiment of the package, the amount of glatiramer acetate may be in the range from 10 to 80 mg; or 12 to 70 g; or 14 to 60 mg; or 16 to 50 mg; or 18 to 40 mg; or 19 to 30 mg; or 20 mg.

_Alternatively, the amount of glatiramer acetate in the package may be in the range from 50 to 150 mg; or 60 to 140 mg; or 70 to 130 mg; or 80 to 120 mg; or 90 to 110 mg; or 100 mg .

For each amount of glatiramer acetate in the package, the amount of simvastatin in the package may be 5-80 mg; or 8-70 mg; or 10- 60 mg; or 12-50 mg; or 14-40 mg; or 16-30 mg; or 18-25 g; or 20 mg.

In one embodiment of the pharmaceutical composition, each of the amount of glatiramer acetate when taken alone and the amount oi simvastatin when taken alone is effective to alleviate the symptom of multiple sclerosis.

In another embodiment of the pharmaceutical composition, either of the amount of glatiramer acetate when taken alone, or the amount of simvastatin when taken alone or each such amount when taken alone is not effective to alleviate the symptom of multiple sclerosis.

The subject invention further provides a pharmaceutical combination comprising separate dosage forms of an amount of glatiramer acetate and an amount of simvastatin, which combination is useful to alleviate a symptom of a form of multiple sclerosis in a subject.

In an embodiment of the pharmaceutical combination, . each of the. amount of glatiramer acetate when taken alone and the amount of simvastatin when taken alone is effective to alleviate the symptom of multiple sclerosis.

In an additional embodiment of the pharmaceutical combination, either of the amount of glatiramer acetate when taken alone, the amount of simvastatin when taken alone or each such amount when taken alone is not effective to alleviate the symptom of multiple sclerosis.

In a further embodiment, the pharmaceutical combination may be for simultaneous, separate or sequential use to treat the foriτ of multiple sclerosis in the subject..

Formulations of the invention suitable lor oral aαministratior. may be in the form of capsules, pills, tablets, powders, granules, or as a solution or a suspension in an aqueous or non- aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using ar. _,

-12- inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of the active compound or compounds .

In solid dosage forms of the invention for oral administration

(capsules, tablets, pills, drageeε, powders, granules and the like), the active ingredient (s) is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalciu phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol/ and/or silicic acid; binders, such as, for example, carboxymethylcelluloεe, alginates, gelatin, polyvinyl pyrrolidone, sucroεe and/or acacia; humectantε, such as glycerol ; disintegrating agents, such as agar-agar, calcium carbonate, calcium phosphate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compoundε; wetting agents, such as, for example, cetyl alcohol and glycerol monos earate; absorbents, such as kaolin and bentonite clay; lubricants, such a talc, calcium εtearate, magnesium εtearate, solid polyethylene glycolε, sodium lauryl sulfate, and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositionε of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycolε and the like.

Liquid dosage forms for oral administration of the active ingredients include pharmaceuticall acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Ir addition to the active ingredient (s) , the liquid dosage forms may contain inert dilutents commonly used in the art, such as, for example, water or other solvents, εolubilizing agents anc e ulsifiers, such aε ethyl alcohol, iεopropyl. alcohol, ethyl carbonate,, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, . castor and sesame oils) , glycerol, tetrahydrofuryl alcohol, polyethylene glycolε and fatty acid esterε of εorbitan, and mixtureε thereof.

Suεpenεionε, in addition. to the active compounds, may contain suspending agents such aε ethoxylated iεoεtearyl alcoholε, polyoxyethylene sorbitoi and εorbitan eεterε, microcryεtalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

The pharmaceutical compoεitionε, particularly those compriεing glatiramer acetate, may also include human adjuvants or carrierε known to thoεe εkilled in the art. Such adjuvants include complete Freund's adjuvant and incomplete Freund's adjuvant. The compositions may also comprise wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Glatiramer acetate may be formulated into pharmaceutical compositions with pharmaceutically acceptable carriers, such aε water or εaline and may be formulated into eye drops . Glatiramer acetate may also be formulated into delivery systems, such as matrix system .

Thiε invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the εpecific methods and results diεcuεsed are merely illustrative of the invention aε described more fully in the claims which follow thereafter. In one embodiment, a product containing glatiramer acetate and simvastatin as a combined preparation for simultaneous, separate or sequential use in therapy; or to alleviate a symptom of a form of multiple sclerosis.

The use of glatiramer acetate and simvastatin for the manufacture of a combined preparation medicament for use to alleviate a symptom of a form of multiple sclerosis, wherein glatiramer acetate and simvastatin are administered simultaneously, separately or sequentially.

The administration of alphacalcidol is at least once every 30 hours for each administration of glatiramer acetate; or at least once every 24 hours for each administration of glatiramer acetate; or is simultaneouε to each administration of glatiramer acetate.

The use of simvastatin for the manufacture of a medicament for use to alleviate or to enhance alleviation of a symptom of a form of multiple scleroεis in a patient who is being treated with glatiramer acetate to alleviate the symptom of a form of multiple sclerosis.

Alternatively, the use of simvastatin for the manufacture of a medicament for use to alleviate a symptom of a form of multiple sclerosis in a patient population that is being treated with glatiramer acetate to alleviate the symptom of a form of multiple scleroεiε. Experimental Details

EXPERIMENT 1: EFFECT OF COPAXONE® AND/OR SIMVASTATIN ON TREATMENT OF EAE

Procedure

This experiment is conducted to evaluate whether the combination of simvastatin and Copaxone® is more effective in alleviating EAE than either alone. EAE is induced in mice by the administration of myelin oligodendrocyte glycoprotein (MOG) . Injection of MOG into C57BL/6 mice produces an acute monophasic EAE (similar to primary progressive multiple sclerosis); injection into 129/SvEv mice, produces a relapsing remitting EAE (murine model of relapsing remitting multiple sclerosis) .

One week before MOG immunization, C57BL/6 and 129/SvEv mice receive a sub-optimal dose of Copaxone® (250 μg per mouse, single injection) alone, simvastatin alone, saline vehicle, or combination of Copaxone® and simvastatin. Over a period of 1-2 months following MOG immunization, clinical scores are monitored by weighing animals on a daily basis and grading the severity of EAE: 0 - no disease; 1 - limp tail; 2 - partial paralysis of one or two hind limbs; 3 - complete paralysis of hind limbs; 4 - hind limb paralysis and fore limb paraparesiε; 5 - moribund. In addition to clinical evaluation, groups of 5 mice are sacrificed at weekly intervals for routine histological examination (hematoxylin-eosin and luxol fast blue for evidence of inflammation and demyelination, respectively) . Also, cellular infiltrates are examined for CD3 (T lymphocytes) , CD56 (natural killer cells) and CD19 (B cell immunohistochemistry) . Loss of neurons and oligodendrocytes is assessed using immunohistochemistry for NeuN and glutathione-S-transferase pi isoform, respectively. Furthermore, axonal integrity is examined using immunohistochemiεtry for β-amyloid precurεor protein or neurofilament, and by Bielchowεky εilver εtains . The neuropathological aεεeεεmentε are focuεed on the optic nerve, lumbar/sacral cord and brain stem.

Results

In comparison to the mice receiving saline vehicle, the mice receiving treatment with Copaxone® alone or simvastatin alone exhibit a lower clinical score and a smaller area under the curve. The administration of the combination of Copaxone® and simvastatin resultε in a score that is comparable or less than the controls. The mice receiving the combination of Copaxone® and simvaεtatin also show an area under the curve that is comparable or less than the controls.

EXAMPLE 2: CLINICAL TRIAL OF RELAPSING-REMITTING MULTIPLE SCLEROSIS

The purpose of this trial is to compare the treatment of participants with relapsing-remitting multiple sclerosis (RR-MS) with COPAXONE® in combination with simvaεtatin, with treatment with COPAXONE® in combination with placebo.. The clinical objective iε to evaluate the effect of treatmentε on MRI variables, clinical evaluations and immunological profile.

The design of this trial is a randomized, double-masked, 2-arm study of COPAXONE® in combination with simvastatin versus COPAXONE® in combination with placebo for the treatment of relapsing-remitting multiple sclerosiε. Twenty patientε with RR- MS who meet the inclusion/exclusion criteria are enrolled per arm. Patientε are randomized and receive either 20 mg SQ (εubcutaneous) of COPAXONE® daily plus an oral dose of placebo daily or 20 mg SQ of COPAXONE® in combination with 50 mg simvastatin every 12 hours .

Participant inclusion criteria are as follows: 1) men or women age 18 to 50 years; 2) RR-MS according to the guidelines from the International Panel on the Diagnosiε of MS (McDonald et al . ) ; 3) two separate documented relapses in the last two years; 4) active MRI with at least one gadolinium(Gd) -enhancing lesion in the MRI scan at screening; 5) EDSS (extended disability status scale) score between 1.0 and 5.0; 6) no relapεe during screening period; 6) pre-treatment with COPAXONE® for at least three weeks, but no more than four weekε, prior to baεeline visit; and 7) ability to underεtand and provide informed consent.

Participant exclusion criteria include the following: 1) normal brain MRI; 2) prior treatment with COPAXONE® other than the scheduled three to four week pretreatment prior to baseline visit; 3) previous treatment with i munomodulating agents such as interferon beta or IVIg for the last 6 months prior to entry; 4) previous use of immunosuppressive agentε (including azathioprine) in the last 12 months prior study entry; 5) steroid treatment one month prior to entry; 6) women not willing to practice reliable methods of contraception; 7) pregnant or nursing women; 8) life threatening or clinically significant diseaεes; 9) hiεtory of alcohol and drug abuse within 6 months prior enrollment; 10) known history of sensitivity to Gd; 11) uncontrolled and uncontrollable head movements (tremor, tics, etc.), muscle spasmε, εignificant urinary urgency and claustrophobia, which will prevent the εubject from lying still during the MRI scan; and 12) participation in other investigational therapy in the last 90 days.

MRI scanε are performed during the screening visit (for eligibility) and at months 5, 10, 11 and 12. Full physical and neurological examinations are performed at screening, baseline and at months 2, 5, 9 and 12. Safety laboratory is performed at screening baseline and at months 1, 2, 5, 9 and 12. In addition, blood Ca⁺ levels are monitored on the first and second monthε after baseline visit. The immunological profile is monitored at baseline and at months 1, 2, 4, and 5.

Primary efficacy endpoints include the following: 1) MRI variables as measured on months 10, 11, and 12; 2) total number and volume of Tl GD-enhanced lesionε; 3) total number of new T2 leεionε; and 4) total volume of T2 leεionε. Secondary efficacy endpoints encompasε the following: 1) changeε in immunological parameterε; and 2) PBMC proliferation in response to GA in vitro. The tertiary efficacy endpoints are as follows: 1) change from baseline in relapse rate and MS Functional Composite Score (MSFC) ; and 2) brain atrophy. Tolerability is evaluated with reference to the following: 1) percentage of subjects who discontinue the study; and 2) percentage of subjects who diεcontinue the εtudy due to adverεe . events. Safety .is evaluated with reference to 1) adverse event frequency and severity; 2) changes in vital signε and 3) clinical laboratory valueε .

Patients treated with the COPAXONE® and simvaεtatin combination exhibit a comparable or greater reduction in Tl and T2 Gd- enhancing leεions and other lesions, as compared to the group receiving COPAXONE® and placebo. Additionally, . the group receiving the COPAXONE® and simvastatin combination demonstrate a comparable or greater reduction in the number of relapses per year as compared with the group receiving COPAXONE® and placebo.

Referenσes

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Claims

What is claimed:

1. A method of treating a subject afflicted with a form of- multiple sclerosiε compriεing periodically administering to the subject an amount of glatiramer acetate and an amount of simvastatin, wherein the amounts when taken together are effective to alleviate a symptom of the form of multiple sclerosis in the subject so as to thereby treat the subject.

2. The method of claim 1, wherein the form of multiple sclerosis is relapsing-remitting multiple εcleroεis.

3. The method of claim 1, wherein the subject iε a human being.

4. 'The method of claim 1, wherein each of the amount of glatiramer acetate when taken alone, and the amount of simvastatin when taken alone is effective to alleviate the symptom of the form of multiple εcleroεiε.

5. The method of claim 1, wherein either the amount of glatiramer acetate when taken alone, the amount of simvastatin when taken alone or each such amount when taken alone is not effective to alleviate the symptom of the form of multiple sclerosis .

6. The method of claim 1, wherein the symptom is the frequency of relapses, the frequency of clinical exacerbation, or the accumulation of physical disability.

7. The method of claim 1, wherein the amount of glatiramer acetate is in the range from 10 to 600 mg/week. -

8. The method of claim 7, wherein the amount of glatiramer acetate is 300 mg/week.

9. The method of claim 1, wherein the amount of glatiramer acetate is in the range from 50 to 150 mg/day.

10. The method of claim 9, wherein the amount of glatiramer acetate is 100 mg/day.

11. The method of claim 1, wherein the amount of glatiramer acetate is in the range from 10 to 80 mg/day.

12. The method of claim 11, wherein the amount of glatiramer acetate is 20 mg/day. ■ •

13. The method of claim 1, wherein the periodic adminiεtration of glatiramer acetate is effected daily.

14. The method of claim 1, wherein the periodic administration of glatiramer acetate is effected twice daily at one half the amount .

15. The method of claim 1, wherein the periodic administration of glatiramer acetate is effected once every 5 to 9 days.

16. The method of claim 1, wherein the administration of the glatiramer acetate substantially precedes the administration of the simvastatin.

17. The method of claim 1, wherein the administration of the simvaεtatin substantially precedes the administration of the glatiramer acetate.

18. The method of claim 1, wherein the administration of the glatiramer acetate is effected subcutaneously , intraperitoneally, intravenously, intramuscularly, intraocularly or orally and the administration of the simvastatin is effected orally.

19. The method of claim 18, wherein the administration of the glatiramer acetate is effected subcutaneously and the administration of the simvastatin is effected orally.

20. A package comprising i) a first pharmaceutical composition comprising an amount of glatiramer acetate and a pharmaceutically acceptable carrier; ii) a second pharmaceutical composition comprising ar amount of simvastatin and a pharmaceutically acceptable carrier; and iii) instructionε for use of the first and seconc pharmaceutical compoεitions together to alleviate c symptom of a form of multiple sclerosiε in a εubject,

21. The package of claim 20, wherein the amount of glatiramer acetate iε 300 mg.

22. The package of claim 20, wherein the amount of glatirame: acetate is 20 mg.

23. A pharmaceutical composition comprising an amount o glatiramer acetate and an amount of simvaεtatin, wherein th amounts when taken together are effective to alleviate a sy pto: of a form of multiple sclerosis in a subject.

24. The pharmaceutical composition of claim 23, wherein each o the amount of glatiramer acetate when taken alone and the amoun of simvaεtatin when taken alone iε effective to alleviate th εymptom of multiple εcleroεiε.

25. The pharmaceutical composition of claim 23, wherein eithe of the amount of glatiramer acetate when taken alone, or tt amount of simvastatin when taken alone or each such amount whe taken alone is not effective to alleviate the symptom c multiple sclerosis.

26. A product containing glatiramer acetate and simvastatin as a combined preparation for simultaneous, separate or sequential use in treating a form of multiple scleroεiε.

27. A product containing glatiramer acetate and εimvastatin as a combined preparation for simultaneous, separate or sequential use in alleviating a symptom of a form of multiple sclerosis.

32. Use of simvastatin for the manufacture of a medicament for use in alleviating a symptom of a form of multiple sclerosiε in a patient who is already being treated with glatiramer acetate.