NZ621215B2 - Treatment of multiple sclerosis with combination of laquinimod and interferon-beta - Google Patents

Abstract

This disclosure provides a method of treating a patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising administering to the patient laquinimod as an add-on therapy to or in combination with interferon-?. This invention also provides a package and a pharmaceutical composition comprising laquinimod and interferon-? for treating a patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome. This disclosure also provides laquinimod for use as an add-on therapy or in combination with interferon-? in treating a patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome. This disclosure further provides use of laquinimod and interferon-? in the preparation of a combination for treating a patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome. utical composition comprising laquinimod and interferon-? for treating a patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome. This disclosure also provides laquinimod for use as an add-on therapy or in combination with interferon-? in treating a patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome. This disclosure further provides use of laquinimod and interferon-? in the preparation of a combination for treating a patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome.

Description

W0 2013I016686 PCT/U52012/048689 TREATMENT OF MULTIPLE SCLEROSIS WITH COMBINATION OF LA!QUINIMOD AND INTERFERON-BETA This application claims benefit of US. Provisional Application No. 61/512,817, filed July 28, 2011, the entire content of which is hereby incorporated by reference .

Throughout this ation, various publications are referred to by first author and year of publication. Full citations for these publications are presented in a References section immediately before the claims. Disclosures of the documents and publications cited are hereby incorporated by reference in their entireties into this application in order to more fully describe the state of the art as of the date ofthe invention described herein. ound Multiple sis (MS) is a neurological disease affecting more than 1 million people worldwide. It is the most common cause of neurological disability in young and middle—aged adults and has a major physical, logical, social and financial impact on subjects and their families, friends and bodies responsible for health care (EMEA Guideline, 2006).

It is generally assumed that MS is mediated by some kind of autoimmune process possibly triggered by infection and superimposed upon a genetic predisposition. It is a chronic inflammatory condition that damages the myelin of the Central Nervous System (CNS). The pathogenesis of MS is characterized by the infiltration of active T—cells from the circulation directed against myelin antigens into the CNS (Bjartmar, 2002). In addition to the inflammatory phase in MS, axonal loss occurs early in the course of the disease and can be extensive over time, leading to the subsequent pment of progressive, permanent, ogic ment and, frequently, severe disability (Neuhaus, 2003). ms associated with the disease include fatigue, spasticity, ataxia, weakness, bladder and bowel bances, sexual ction, pain, tremor, paroxysmal manifestations, visual impairment, psychological problems and cognitive dysfiinction (EMEA Guideline, 2006).MS e activity can be monitored by cranial scans, including magnetic resonance imaging (MRI) of the brain, accumulation of disability, as well as rate and severity of relapses. The diagnosis of clinically definite MS as determined by the Poser criteria (Poser, 1983) requires at least two neurological events suggesting demyelination in the CNS separated in time and in location. A clinically isolated syndrome (CIS) is a single monosymptomatic attack suggestive of MS, such as optic neuritis, brain stem symptoms, and l myelitis. Patients with CIS that experience a second al attack are generally considered to have ally definite multiple sclerosis (CDMS). Over 80 percent of ts with a CIS and MR1 lesions go on to develop MS, while approximately 20 percent have a self—limited process (Brex, 2002; Frohman, 2003).

W0 20131016686 PCT/U82012/048689 Various MS disease stages and/or types are described in Multiple Sclerosis Therapeutics (Duntiz, 1999). Among them, relapsing-remitting multiple sclerosis (RRMS) is the most common form at the time of initial diagnosis. Many ts with RRMS have an initial relapsing—remitting course for 5- years, which then advances into the secondary ssive MS (SPMS) disease course. Relapses result from inflammation and demyelination, s restoration of nerve conduction and remission is accompanied by resolution of inflammation, redistribution of sodium channels on demyelinated axons and remyelination (Neuhaus, 2003; Noseworthy, 2000).

In April 2001, an international panel in association with the National MS Society of America recommended diagnostic ia for multiple sis. These criteria became known as the McDonald ia. The McDonald Criteria make use of MRI techniques and are intended to e the Poser Criteria and the older Schumacher Criteria (McDonald, 2001). The McDonald ia was d in March 2005 by an international panel (Polman, 2005) and updated again in 2010 (Polman, 2011).

Intervention with disease-modifying therapy at relapsing stages of MS is suggested to reduce and/or prevent accumulating neurodegeneration (Hohlfeld, 2000; De Stefano, 1999). There are currently a number of disease—modifying medications ed for use in relapsing MS (RMS), which includes RRMS and SPMS (The Disease Modifying Drug Brochure, 2006). These e interferon beta l-a (Avonex® and Rebif®), interferon beta l-b (Betaseron®), glatiramer acetate (Copaxone®), ntrone (Novantrone®), natalizumab (Tysabri®) and fingolimod (Gilenya®). Most of them are ed to act as immunomodulators. Mitoxantrone and natalizumab are believed to act as immunesuppressants. However, the mechanisms of action of each have been only partly elucidated.

Immunosuppressants or cytotoxic agents are used in some subjects after failure of conventional therapies. However, the relationship between s of the immune response induced by these agents and the clinical efficacy in MS is far from settled (EMEA Guideline, 2006).

Other therapeutic approaches include symptomatic treatment which refers to all therapies applied to improve the symptoms caused by the disease (EMEA Guideline, 2006) and ent of acute relapses with corticosteroids. While ds do not affect the course of MS over time, they can reduce the duration and severity of attacks in some subjects.

Laquinimod Laquinimod is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) (Pohnan, 2005; Sandberg-Wollheim, 2005). Laquinimod and its sodium salt form are described, for example, in US. Patent No. 6,077,851.

PCT/U82012/048689 The mechanism of action of imod is not fiilly understood. Animal studies show it causes a Thl (T helper 1 cell, produces pro-inflammatory cytokines) to Th2 (T helper 2 cell, produces anti- inflammatory nes) shift with an anti-inflammatory profile (Yang, 2004; Brfick, 2011). Another study demonstrated (mainly via the NFkB pathway) that laquinimod induced suppression of genes related to antigen presentation and corresponding inflammatory ys (Gurevich, 2010). Other suggested potential mechanisms of action include inhibition of leukocyte migration into the CNS, se of axonal integrity, modulation of cytokine production, and increase in levels of brain— derived neurotrophic factor (BDNF) (Runstrom, 2006; Briick, 2011).

Laquinimod showed a favorable safety and tolerability profile in two phase III trials (Results of Phase III BRAVO Trial Reinforce Unique Profile of Laquinimod for Multiple sis Treatment; Teva Pharma, Active Biotech Post Positive Laquinimod Phase 3 ALLEGRO s).

Interferon beta (IFN—lfl) Interferons (IFNs) are cytokines produced and released by host cells in response to the presence of pathogens and allow ication between cells to trigger the protective defenses of the immune system. lFN—B has been used over that past 15 years as treatment for RRMS. IFNs’ complex mechanisms of action are not yet completely elucidated. Commercially available IFN-B include Avonex®, Betaseron®, Extavia® and Rebif®.

Add-On/Combination Therapy The effects of add-0n or combination y using laquinimod and interferon—B on MS patients have not been reported.

The administration of two drugs to treat a given condition, such as 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 the effects of the other. For ce, one drug may t, te or induce the production of enzymes involved in a lic route of elimination of the other drug (Guidance for Industry, 1999).

In one example, combined administration of GA and interferon (IFN) has been experimentally shown to abrogate the clinical effectiveness of either therapy (Brod 2000). In another experiment, it was reported that the addition of prednisone in ation therapy with IFN—B antagonized its up- regulator . Thus, when two drugs are administered to treat the same condition, it is ictable whether each will complement, have no effect on, or interfere with, the therapeutic activity of the other in a human subject.

PCT/U82012/048689 Not only may the interaction between two drugs affect the intended therapeutic activity of each drug, but the ction may se the levels of toxic metabolites (Guidance for Industry, 1999). 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. In one example, the combination of natalizumab and interferon B-la was observed to increase the risk of unanticipated side effects (Vollmer, 2008; Rudick 2006; Kleinschmidt—DeMasters, 2005; Langer—Gould 2005).

Additionally, it is difficult to accurately predict when the effects of the interaction between the two drugs will become manifest. For example, metabolic interactions n drugs may become apparent upon the initial administration of the second drug, after the two have reached a steady—state tration or upon discontinuation of one of the drugs (Guidance for Industry, 1999). ore, the state of the art at the time of filing is that the effects of an add-on or ation therapy of two drugs, in particular laquinimod and IFN—B, cannot be predicted until the results of a formal combination study are available.

W0 2013(016686 PCT/U82012/048689 Brief Description of the Drawings Figure 1: Figure 1 is a graphical representation of the activity of interferon-B stered daily, subcutaneous (5.0). alone or in combination with laquinimod in chronic EAE in C57 BI mice. The graph shows the mean clinical score for the EAE rodents in each group (on the y—axis) against the days (on the X—axis). y of the Invention In a first aspect, the present invention provides the use of 0.6mg laquinimod in the manufacture of a medicament for the ent of a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the medicament is prepared as an add-on therapy to or in combination with an amount of interferon—B, wherein the amounts when taken together is more effective to treat the human patient than when each agent at the same amount is administered alone.

In another aspect, the present invention provides the use of 0.6mg laquinimod and an amount of interferon-l3 in the manufacture of a medicament for the treatment of a human patient afflicted with le sclerosis or presenting a ally isolated syndrome, wherein the amounts when taken together is more effective to treat the human patient than when each agent at the same amount is administered alone.

In another aspect the present invention provides the use of an amount of laquinimod in the manufacture of a medicament for the treatment of a human patient ed with multiple sclerosis or presenting a clinically isolated syndrome, wherein the medicament is prepared as an add-on therapy to or in combination with an amount of interferon-B (IFN—B), n the amounts when taken together are more effective to treat the human patient than when each agent at the same amount is administered alone.

In a further aspect, the present invention es the use of an amount of laquinimod and an amount of interferon-B in the manufacture of a medicament for the treatment of a human patient afflicted with le sclerosis or presenting a clinically isolated syndrome, wherein the s when taken together are more effective to treat the human t than when each agent at the same amount is administered alone.

In a still further aspect, the t invention provides a package comprising: a) a first pharmaceutical composition comprising an amount of laquinimod and a pharmaceutically acceptable carrier; b) a second pharmaceutical ition comprising an amount of interferon-6 and a pharmaceutically acceptable carrier; and instructions for use of the first and second pharmaceutical compositions er to treat a human patient afflicted with multiple sclerosis or presenting a clinically isolated me, wherein the amount of laquinimod and the amount of interferon-6 when taken together are more effective to treat the human patient than each agent at the same amount is administered alone.

This invention provides a method of treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising orally administering to the patient a daily dose of 0.6mg laquinimod, and periodically administering to the patient a pharmaceutically effective amount of interferon-B, wherein the amounts when taken together is more effective to treat the human patient than when each agent is administered alone.

This invention provides a method of treating a human t afflicted with multiple sclerosis or presenting a clinically isolated syndrome sing periodically administering to the patient an amount of laquinimod and an amount of interferon-B, wherein the amounts when taken er are effective to treat the human patient.

This invention also provides a package comprising a) a first pharmaceutical composition comprising an amount of laquinimod and a pharmaceutically acceptable carrier; b) a second pharmaceutical ition comprising an amount of interferon—B and a pharmaceutically acceptable carrier; and c) instructions for use of the first and second ceutical itions together to treat a human patient afflicted with multiple sclerosis or ting a clinically isolated syndrome.

This invention also provides laquinimod for use as an add-on therapy or in combination with interferon-fl in treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome.

This invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amount of interferon-B for use in treating a human patient afflicted with le sclerosis or presenting a clinically isolated syndrome, wherein the laquinimod and the interferon-6 are administered simultaneously or contemporaneously.

This invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amount of interferon-B.

This invention also provides use of an amount of laquinimod and an amount of interferon-B in the preparation of a combination for ng a human patient afflicted with multiple sclerosis or ting a clinically isolated syndrome wherein the laquinimod and the eron-B are administered simultaneously or poraneously.

This ion also es pharmaceutical ition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome as an add-on therapy or in combination with interferon-ti by periodically administering the pharmaceutical composition and the interferon-B to the subject.

This invention r provides pharmaceutical composition comprising an amount of interferon-B for use treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome as an add-on therapy or in combination with laquinimod by periodically administering the pharmaceutical ition and the laquinimod to the subject.

WO 16686 PCT/U82012/048689 Detailed Description of the Invention This invention provides a method of treating a human patient afflicted with le sclerosis or presenting a clinically isolated syndrome comprising orally administering to the patient a daily dose of 0.6mg imod, and periodically administering to the patient a pharmaceutically effective amount of interferon—B, wherein the amounts when taken together is more effective to treat the human t than when each agent is administered alone.

In one embodiment, the multiple sclerosis is relapsing multiple sis. In another embodiment, the ing le sclerosis is relapsing-remitting multiple sclerosis.

In one ment, the amount of imod and the amount of interferon-[3 when taken together is effective to reduce a symptom of multiple sclerosis in the human t. In another ment, the symptom is a MRI—monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, frequency of al exacerbation, brain atrophy, risk for confirmed progression, or time to confirmed disease progression.

In one embodiment, the accumulation of physical disability is assessed by the time to confirmed disease ssion as measured by Kurtzke Expanded Disability Status Scale (EDSS) score. In another embodiment, the patient had an EDSS score of 0—5 prior to administration of laquinimod. In another embodiment, the patient had an EDSS score of 1-5 .5 prior to administration of imod. In another embodiment, the patient had an EDSS score of 0-5.5 prior to stration of laquinimod. In another embodiment, the patient had an EDSS score of 5.5 or greater prior to administration of laquinimod. In another embodiment, confirmed disease progression is a I point increase of the EDSS score. In yet another embodiment, confirmed disease progression is a 0.5 point increase of the EDSS score.

In one embodiment, time to confirmed disease progression is increased by 10-100%. In another embodiment, time to confirmed disease progression is increased by 20—80%. In another embodiment, time to confirmed disease progression is increased by 20-60%. In another embodiment, time to confirmed disease progression is increased by 30—50%. In yet another embodiment, time to confirmed disease progression is increased by at least 50%.

In one embodiment, laquinimod is laquinimod sodium. In another embodiment, the interferon-[3 is administered via subcutaneous injection or intramuscular injection.

In one ment, the interferon-l3 is interferon beta-la. In another embodiment, the interferon-[3 is interferon beta~lb.

In one embodiment, the interferon—B is administered intramuscularly. In another embodiment, the interferon—B is stered subcutaneously. In another embodiment, the interferon-B is administered PCT/U82012/048689 1-5 times a month. In another embodiment, the interferon-B is stered 1-3 times a month. In another embodiment, the interferon-l3 is administered 1-5 times a week. In another embodiment, the interferon—B is administered 1—3 times a week. In r embodiment, the interferon—B is administered 1-5 times a day. In another embodiment, the interferon-B is administered 1-3 times a day. In another embodiment, the interferon-B is administered every other day. In yet another embodiment, the eron-B is stered daily.

In one embodiment, the amount interferon—B stered is about 10-300 meg. In another embodiment, the amount interferon-B administered is about 30-250 meg. In another embodiment, the amount interferon—B administered is about 30-440 meg. In another embodiment, the amount interferon—B administered is about 22-44 meg. In another embodiment, the amount interferon—B administered is about 30 meg. In another embodiment, the amount eron-[3 administered is about 250 meg.

In one embodiment, the interferon-B is interferon beta-1a and is administered intramuscularly at 30 mcg, once weekly. In another embodiment, the interferon-[3 is interferon beta-lb and is administered subcutaneously at 0.25 mg, every other day. In another embodiment, the interferon-B is interferon b and is stered subcutaneously at 0.25 mg, every other day. In yet another embodiment, the eron-[3 is interferon beta-1a and is administered subcutaneously at 22-44 meg, three times a week.

In one embodiment, the administration of laquinimod substantially precedes the administration of interferon—B. In another embodiment, the administration of interferon—B substantially precedes the administration of laquinimod.

In an embodiment, the human patient is receiving interferon-[3 therapy prior to initiating laquinimod therapy. In another embodiment, the human t is receiving interferon-B therapy for at least 24 weeks prior to initiating laquinimod therapy. In another ment, the human patient is receiving interferon—B therapy for about 24 weeks prior to initiating imod therapy. In r embodiment, the human patient is receiving interferon-B therapy for at least 28 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is ing interferon—[3 therapy for about 28 weeks prior to initiating laquinimod therapy. In another embodiment, the human t is receiving eron—B therapy for at least 48 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving interferon-B therapy for about 48 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving interferon-B therapy for at least 52 weeks prior to initiating laquinimod therapy. In yet another ment, the human patient is receiving interferon-B therapy for about 52 weeks prior to initiating laquinimod therapy.

PCT/U82012/048689 In one embodiment, the laquinimod is administered in the morning. In another embodiment, the laquinimod is administered at night. In one embodiment, the laquinimod is with food. In another embodiment, the laquinimod is administered without food.

In one embodiment, the eron-B is administered in the morning. In another embodiment, the interferon—B is administered at night. In one embodiment, the interferon—B is administered with food. In another embodiment, the interferon—B is administered without food.

In one embodiment, the laquinimod is stered simultaneously with the interferon-B. In another embodiment, the imod is administered contemporaneously with the interferon—B. In another embodiment, the laquinimod is administered immediately before or immediately after the interferon~{3.

In another embodiment, the laquinimod is administered within 1 hour before or after the interferon— B. In another embodiment, the laquinimod is administered within 3 hour before or after the interferon~B. In another embodiment, the laquinimod is stered within 6 hour before or after the eron—[3. In another embodiment, the laquinimod is stered within 12 hour before or after the interferon-B. In another embodiment, the laquinimod is administered within 24 hour before or after the interferon—B.

In one embodiment, the method further comprises administration of nonsteroidal anti-inflammatory drugs (NSAIDS), salicylates, slow-acting drugs, gold compounds, hydroxychloroquine, sulfasalazine, combinations of slow-acting drugs, corticosteroids, cytotoxic drugs, immunosuppressive drugs and/or antibodies.

In an ment, the periodic administration of laquinimod and interferon-B ues for more than 30 days. In another embodiment, the ic stration of laquinimod and interferon—B continues for more than 42 days. In yet another embodiment, the periodic administration of imod and interferon-B continues for 6 months or more.

In one embodiment, the administration of laquinimod and interferon-[3 inhibits a symptom of relapsing multiple sclerosis by at least 20%. In another embodiment, the administration of laquinimod and interferon-B ts a symptom of relapsing multiple sclerosis by at least 30%. In another embodiment, the administration of laquinimod and interferon-B inhibits a symptom of relapsing multiple sclerosis by at least 40%. In another embodiment, the administration of laquinimod and eron-B ts a symptom of relapsing multiple sclerosis by at least 50%. In another embodiment, the administration of laquinimod and interferon-B inhibits a symptom of ing le sclerosis by more than 100%. In another ment, the administration of laquinimod and interferon-B ts a symptom of relapsing multiple sclerosis by more than 300%. In yet another embodiment, the administration of laquinimod and interferon—B inhibits a symptom of relapsing multiple sclerosis by more than 1000%.

W0 16686 2012/048689 In one embodiment, each of the amount of laquinimod when taken alone, and the amount of interferon- B when taken alone is effective to treat the human patient. In another embodiment, either the amount of laquinimod when taken alone, the amount of interferon-B when taken alone, or each such amount when taken alone is not effective to treat the human patient.

This invention also provides a method of treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome comprising periodically stering to the patient an amount of laquinimod and an amount of interferon—B (IFN-B), wherein the amounts when taken together are effective to treat the human patient. In one embodiment, the amount of laquinimod and the amount of IFN—[i when taken together is more effective to treat the human patient than when each agent is administered alone.

In one embodiment, the multiple sclerosis is relapsing multiple sclerosis. In another embodiment, the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis.

In one embodiment, the amount of laquinimod and the amount of interferon-B when taken together is effective to reduce a symptom of multiple sclerosis in the human patient. In another embodiment, the symptom is a MRI—monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, decreased time to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal sis, risk for confirmed progression, deterioration of visual function, e, impaired mobility, cognitive impairment, reduction of brain volume, 2O abnormalities observed in whole Brain MTR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work.

In one embodiment, the amount of imod and the amount of interferon—B when taken together is effective to se or inhibit reduction of brain volume. In another embodiment, brain volume is ed by percent brain volume change (PBVC).

In one ment the amount of laquinimod and the amount of eron—[3 when taken together is effective to increase time to confirmed disease progression. In another embodiment, time to confirmed disease progression is increased by 20—60%. In yet another embodiment, time to confirmed disease progression is increased by at least 50%.

In one ment, the amount of laquinimod and the amount of interferon-B when taken together is effective to decrease abnormalities observed in whole Brain MTR ram.

In one embodiment, the accumulation of physical lity is measured by Kurtzke Expanded Disability Status Scale (EDSS) score. In another embodiment, the accumulation of physical disability is assessed by the time to confirmed disease progression as ed by Kurtzke Expanded Disability Status Scale (EDSS) score. In another embodiment, the patient had an EDSS score of 0—5.5 prior to administration of laquinimod. In another embodiment, the patient had an EDSS score of 1.5—4.5 prior to administration of laquinimod. In another embodiment, the patient had an EDSS score of 5.5 or r prior to administration of laquinimod. In another embodiment, confirmed disease ssion is a 1 point increase of the EDSS score. In yet r embodiment, ed disease progression is a 0.5 point increase of the EDSS score.

In one ment, impaired mobility is assessed by the Timed—25 Foot Walk test. In r embodiment, impaired mobility is assessed by the 12-Item Multiple Sclerosis Walking Scale (MSWS- 12) self—report questionnaire. In another embodiment, ed mobility is assessed by the Ambulation Index (AI). In another embodiment, impaired mobility is assessed by the Six~Minute Walk (6MW) Test. In yet another embodiment, impaired mobility is assessed by the Lower Extremity Manual Muscle Test (LEMMT) Test.

In one embodiment, the amount of laquinimod and the amount of interferon-B when taken together is effective to reduce ive impairment. In another embodiment, cognitive impairment is assessed by the Symbol Digit Modalities Test (SDMT) score.

In one embodiment, general health status is assessed by the EuroQoL (EQSD) questionnaire, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC). In another embodiment, functional status is measured by the patient’s Short—Form l Health survey (SF—36) Subject Reported Questionnaire score. In another ment,quality of life is assessed by SF—36, EQSD, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC). In another embodiment, the patient’s SF—36 mental component y score (MSC) is improved. In another embodiment, the patient’s SF-36 physical component summary sore (PSC) is improved.

In one embodiment, fatigue is assessed by the EQSD, the patient’s Modified e Impact Scale (MFIS) score or the French valid versions of the e Impact Scale (EMIF-SEP) score. In another embodiment,symptom ty on work is ed by the work productivity and activities impairment General Health (WPAI-GH) questionnaire.

In one embodiment, laquinimod is laquinimod sodium. In another embodiment, laquinimod is administered via oral administration. In another embodiment, laquinimod is administered daily. In another embodiment, laquinimod is administered more often than once daily. In another embodiment, laquinimod is administered less often than once daily.

In one embodiment, the amount laquinimod administered is less than 0.6 . In another embodiment, the amount laquinimod administered is 0.1-40.0 mg/day. In another embodiment, the W0 20131’016686 amount laquinimod administered is 0.1—2.5 . In another embodiment, the amount imod administered is 0.25-2.0 . In another embodiment, the amount imod administered is 0.5-1.2 mg/day. In another embodiment, the amount laquinimod administered is 0.25 mg/day. In another embodiment, the amount laquinimod administered is 0.3 mg/day. In another embodiment, the amount laquinimod administered is 0.5 y. In another embodiment, the amount imod administered is 0.6 mg/day. In another embodiment, the amount laquinimod administered is 1.0 mg/day. In another embodiment, the amount laquinimod administered is 1.2 mg/day. In r embodiment, n the amount laquinimod administered is 1.5 mg/day. In another embodiment, the amount laquinimod administered is 2.0 mg/day.

In one embodiment, a loading dose of an amount different form the intended dose is administered for a period of time at the start of the periodic stration. In another ment, the g dose is double the amount of the ed dose. In yet another embodiment, the g dose administered for two days at the start of the periodic administration.

In one embodiment, the eron-B is administered via subcutaneous injection or intramuscular injection. In another embodiment, the interferon-[3 is interferon beta-Ia and is administered intramuscularly at 30 mcg, once weekly. In another embodiment, the interferon—B is interferon beta-lb and is administered subcutaneously at 0.25 mg, every other day. In another embodiment, the interferon- I3 is interferon beta-1b and is administered subcutaneously at 0.25 mg, every other day. In another embodiment, the eron—B is interferon beta-1a and is administered subcutaneously at 22-44 mcg, 2O three times a week.

In one embodiment, the administration of laquinimod substantially precedes the administration of interferon—B. In another embodiment, the administration of interferon—B ntially precedes the administration of Iaquinirnod. In another embodiment, the human patient is receiving interferon-B therapy prior to initiating imod therapy. In another embodiment, the human patient is receiving interferon—B therapy for at least 24 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving interferon-B therapy for at least 28 weeks prior to initiating laquinimod therapy. In another embodiment, the human patient is receiving interferon-B therapy for at least 48 weeks prior to ting laquinimod therapy. In another embodiment, the human patient is receiving interferon-B therapy for at least 52 weeks prior to initiating laquinimod therapy.

In an ment, the method further comprises administration of nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, slow-acting drugs, gold compounds, hydroxychloroquine, sulfasalazine, combinations of slow-acting drugs, corticosteroids, cytotoxic drugs, immunosuppressive drugs and/or antibodies.

PCT/U82012/048689 In one embodiment, the periodic administration of laquinimod and interferon—[3 continues for at least 3 days. In r ment, the ic administration of laquinimod and interferon—B ues for more than 30 days. In another embodiment, the periodic administration of imod and interferon—B continues for more than 42 days. In another embodiment, the periodic administration of laquinimod and interferon-B continues for 8 weeks or more. In another ment, the periodic administration of laquinimod and interferon-B continues for at least 12 weeks. In another embodiment, the periodic administration of laquinimod and interferon—B continues for at least 24 weeks. In another embodiment, the periodic administration of laquinimod and interferon-B continues for more than 24 weeks. In another embodiment, the periodic administration of laquinimod and interferon—{3 continues for 6 months or more.

In an embodiment, the administration of laquinimod and interferon-B inhibits a symptom of relapsing multiple sclerosis by at least 20%. In another embodiment, the stration of laquinimod and interferon—B inhibits a symptom of ing le sclerosis by at least 30%. In r embodiment, the administration of laquinimod and interferon-B ts a symptom of relapsing multiple sclerosis by at least 50%. In another embodiment, the administration of laquinimod and interferon—B inhibits a m of relapsing multiple. sclerosis by at least 70%. In another embodiment, the administration of laquinimod and interferon—B inhibits a symptom of relapsing multiple sis by more than 100%. In another embodiment, the administration of laquinimod and interferon-[i inhibits a m of relapsing multiple sclerosis by more than 300%. In yet another embodiment, the administration of laquinimod and interferon-[3 ts a symptom ofrelapsing multiple sclerosis by more than 1000%. 2O In one embodiment, each of the amount of laquinimod when taken alone, and the amount of interferon- {3 when taken alone is effective to treat the human patient. In another embodiment, either the amount of laquinimod when taken alone, the amount of interferon-B when taken alone, or each such amount when taken alone is not effective to treat the human patient.

This invention also provides a package comprising a) a first pharmaceutical composition comprising an amount of laquinimod and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising an amount of interferon—[3 and a pharmaceutically acceptable carrier; and c) instructions for use of the first and second ceutical compositions together to treat a human patient afflicted with multiple sclerosis or presenting a ally isolated syndrome.

In one embodiment, the first pharmaceutical composition is in liquid form. In another embodiment, the first pharmaceutical composition is in solid form. In another embodiment, the first pharmaceutical composition is in capsule form. In r embodiment, the first pharmaceutical ition is in tablet form. In another embodiment, the tablets are coated with a coating which inhibits oxygen from contacting the core. In another embodiment, the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, and pigment.

W0 2013f016686 PCTfU82012/048689 In one embodiment, the first ceutical composition further comprises mannitol. In another embodiment, the first pharmaceutical composition further comprises an alkalinizing agent. In another embodiment, the alkalinizing agent is ine. In another embodiment, the first pharmaceutical composition further comprises an oxidation reducing agent.

In one embodiment, the first pharmaceutical composition is stable and free of an nizing agent or an oxidation reducing agent. In another embodiment, the first pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.

In one embodiment, the first ceutical composition is stable and free of disintegrant. In another embodiment, the first pharmaceutical composition further comprises a ant. In another embodiment, the lubricant is present in the composition as solid particles. In another embodiment, the lubricant is sodium stearyl fumarate or magnesium stearate.

In one embodiment the first ceutical composition r comprises a filler. In another embodiment, the filler is t in the composition as solid particles. In another embodiment, the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a ation thereof. In another embodiment, the filler is mannitol or lactose monohydrate.

In one embodiment, the package filrther ses a desiccant. In another embodiment, the desiccant is silica gel.

In an embodiment, the first pharmaceutical composition is stable has a moisture content of no more than 4%. In another embodiment, laquinimod is present in the composition as solid particles.

In an embodiment, the package is a sealed packaging having a moisture bility of not more than mg/day per liter. In r embodiment, the sealed package is a blister pack in which the maximum moisture permeability is no more than 0.005 mg/day. In another embodiment, the sealed package is a bottle. In another embodiment, the bottle is closed with a heat induction liner. In another embodiment, the sealed e comprises an HDPE bottle. In another embodiment, the sealed package comprises an oxygen absorbing agent. In another embodiment, the oxygen absorbing agent is iron.

In an embodiment, the amount of laquinimod in the first composition is less than 0.6 mg. In another embodiment,the amount of laquinimod in the first ition is 01-400 mg. In another embodiment,the amount of laquinimod in the first composition is 0.1-2.5 mg. In another embodiment, the amount of laquinimod in the first composition is 025-20 mg. In another embodiment, the amount of laquinimod in the first composition is 0.5 -1 .2 mg. In another ment,the amount of laquinimod PCT/U$2012/048689 in the first composition is 0.25 mg. In another embodiment, the amount of laquinimod in the first composition is 0.3 mg. In another embodiment, the amount of laquinimod in the first composition is 0.5 mg. In another ment, the amount of imod in the first composition is 0.6 mg. In another embodiment,the amount of laquinimod in the first composition is 1.0 mg. In another embodiment, the amount of laquinimod in the first composition is 1.2 mg. In another embodiment, the amount of laquinimod in the first composition is 1.5 mg. In yet another embodiment, the amount of laquinimod in the first composition is 2.0 mg.

This invention also es laquinimod for use as an add—on therapy or in combination with interferon—[3 in treating a human patient afflicted with multiple sclerosis or ting a clinically isolated syndrome.

This invention also provides a pharmaceutical ition comprising an amount of laquinimod and an amount of interferon-B for use in treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated me, n the laquinimod and the interferon-B are administered simultaneously or poraneously.

This invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amount of interferon—B.

In one ment, the pharmaceutical composition is in liquid form. In r embodiment, the pharmaceutical composition is in solid form. In another embodiment, the pharmaceutical composition is in capsule form. In another embodiment, the pharmaceutical composition is in tablet form. In another embodiment, the tablets are coated with a coating which inhibits oxygen from contacting the core. . In another embodiment, the coating ses a cellulosic polymer, a detackifier, a gloss enhancer, and pigment.

In one embodiment, the pharmaceutical composition further comprises mannitol. In another embodiment, the pharmaceutical composition further comprises an alkalinizing agent. In another embodiment, the alkalinizing agent is meglumine. In yet another embodiment, the pharmaceutical composition further comprises an oxidation ng agent.

In one embodiment, the pharmaceutical composition is free of an nizing agent or an oxidation reducing agent. In another embodiment, the pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.

In one embodiment, the pharmaceutical composition is stable and free of disintegrant. In another embodiment, the pharmaceutical composition further comprises a ant. In r embodiment, PCT/U82012/048689 the lubricant is present in the composition as solid particles. In r ment, the lubricant is sodium stearyl fumarate or magnesium stearate.

In an embodiment, the pharmaceutical composition further sesa filler. In another embodiment, the filler is present in the composition as solid les. In another embodiment, the filler is lactose, e drate, starch, isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof. In another embodiment, the filler is mannitol or lactose monohydrate.

In an embodiment, the amount of laquinimod in the composition is less than 0.6 mg. In another embodiment, the amount of laquinimod in the composition is 01-400 mg. In another embodiment, the amount of laquinimod in the composition is 0.1-2.5 mg. In another ment, the amount of laquinimod in the composition is .0 mg. In another embodiment, the amount of laquinimod in the ition is 0.5—1.2 mg. In another embodiment, the amount of laquinimod in the composition is 0.25 mg. In another embodiment, the amount of laquinimod in the composition is 0.3 mg. In another embodiment, the amount of laquinimod in the composition is 0.5 mg. In another embodiment, the amount of imod in the composition is 0.6 mg. In another embodiment, the amount of laquinimod in the composition is 1.0 mg. In another embodiment, the amount of laquinimod in the composition is 1.2 mg. In another embodiment, the amount of laquinimod in the composition is 1.5 mg. In yet another embodiment, the amount of laquinimod in the composition is 2.0 mg.

This invention further provides use of an amount of laquinimod and an amount of interferon-B in the preparation of a combination for treating a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome wherein the laquinimod and the interferon-B are administered simultaneously or contemporaneously.

This invention also provides pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with multiple sclerosis or presenting a ally isolated syndrome as an add—on y or in combination with interferon—B by ically administering the pharmaceutical composition and the interferon—B to the subject.

This invention further provides pharmaceutical composition sing an amount of interferon-B for use treating a subject afflicted with multiple sclerosis or presenting a clinically isolated syndrome as an add-on therapy or in combination with laquinimod by periodically administering the pharmaceutical composition and the laquinimod to the subject.

For the foregoing embodiments, each embodiment disclosed herein is plated as being applicable to each of the other disclosed embodiments. In addition, the elements recited in the W0 2013f016686 PCT/U82012/048689 packaging and pharmaceutical composition embodiments can be used in the method ments described .

Laguinimod Laquinimod mixtures, compositions, and the process for the manufacture thereof are described in, e.g., U.S. Patent No. 6,077,851, U.S. Patent no. 7,884,208, U.S. Patent No. 7,989,473, U.S. Patent No. 8,178,127, U.S. Application Publication No. 2010-0055072, U.S. Application Publication No. 2012—0010238, and U.S. Application Publication No. 2012-0010239, each of which is hereby incorporated by reference in its entireties into this application.

Use of laquinimod for treatment of various conditions, and the corresponding dosages and regimens, are described in U.S. Patent No. 851 (multiple sclerosis, n—dependent diabetes mellitus, systemic lupus matosus, rheumatoid arthritis, inflammatory bowel disease, psoriasis, inflammatory respiratory disorder, atherosclerosis, stroke, and Alzhemier’s disease), U.S. Application Publication No. 2011-0027219 (Crohn’s disease), U.S. Application Publication No. 2010-0322900 (Relapsing-remitting multiple sclerosis), U.S. Application Publication No. 2011—0034508 (brain- derived neurotrophic factor —related diseases), U.S. Application ation No. 2011- 0218179 (active lupus nephritis), U.S. Application Publication No. 2011-0218203 atoid arthritis), U.S. Application Publication No. 2011-0217295 (active lupus arthritis), and U.S.

Application Publication No. 2012—0142730 (reducing fatigue, improving quality of life, and providing neuroprotection in MS patients), each of which is hereby incorporated by reference in its 2O entireties into this application.

Commercially Available Interferon Beta (IFN-B) Commercially available IFN—B include ®, Betaseron®, Extavia® and . The recommended Avonex® dose for treating MS is 30 mcg injected into a muscle once weekly. The recommended ron® dose for treating MS is 0.25 mg injected (subcutaneously) every other day.

The recommended Extavia® dose for treating MS is 0.25 mg, injected subcutaneously every other day. The recommended dose of Rebif® for treating MS is 22 mcg or 44 meg, injected subcutaneously three times a week.

A pharrnaceutically acceptable salt of laquinimod as used in this application includes m, sodium, potassium, magnesium, calcium, manganese, , zinc, aluminum and iron. Salt formulations of laquinimod and the process for preparing the same are described, e. g., in U.S. Patent No. 7,589,208 and PCT ational Application Publication No. , which are hereby incorporated by reference into this application.

Laquinimod can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically able carrier) suitably ed with respect to the intended form of stration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral administration.

Laquinimod can be administered alone but is generally mixed with a aceutically acceptable carrier, and co—administered in the form of a tablet or capsule, liposome, or as an agglomerated powder. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. e or tablets can be formulated and made easy to swallow or chew; other solid forms include granules, and bulk powders.

Tablets may contain suitable binders, lubricants, disintegrating agents (disintegrants), coloring , flavoring agents, flow—inducing agents, and g agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined with an oral, non- toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, , sucrose, glucose, methyl cellulose, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and tic gums such as , tragacanth, or sodium te, povidone, carboxymethylcellulose, polyethylene glycol, waxes, and the like. ants used in these dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like. Disintegrators (disintegrants) include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate and the like.

Specific es of the techniques, pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described, e.g., in US. Patent No. 7,589,208, PCT International Application Publication Nos. , , and 2007/146248.

General techniques and compositions for making dosage forms useful in the present invention are described in the following references: Modern Pharmaceutics, rs 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. 3O (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds, 1992); Advances in ceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds, 1995); Aqueous ric Coatings for ceutical Dosage Forms (Drugs and the Pharmaceutical es, Series 36 (James McGinity, Ed, 1989); Pharmaceutical Particulate Carriers: eutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed, 1993); Drug Delivery to the Gastrointestinal PCT/U82012/048689 Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G.

Hardy, S. S. Davis, Clive G. Wilson, Eds).; Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds). These nces in their entireties are hereby incorporated by nce into this application.

Disclosed is a method for ng a human patient afflicted with relapsing multiple sclerosis using laquinimod with interferon-[3 which provides a more efficacious treatment than each agent alone. The use of laquinimod for relapsing multiple sclerosis had been previously suggested in, e. g., US. Patent No. 6,077,851. However, the inventors have surprisingly found that the combination of imod and interferon-beta (IFN—B) is particularly effective for the treatment of relapsing multiple sclerosis as compared to each agent alone.

Terms As used herein, and unless stated otherwise, each of the following terms shall have the definition set forth below.

As used herein, “laquinimod” means laquinimod acid or a ceutically acceptable salt thereof.

As used , an “amount” or “close” of imod as measured in milligrams refers to the milligrams of laquinimod acid present in a ation, regardless of the form of the preparation. A “dose of 0.6 mg laquinimod” means the amount of laquinimod acid in a preparation is 0.6 mg, regardless of the form of the ation. Thus, when in the form of a salt, cg. a laquinimod sodium salt, the weight of the salt form necessary to provide a dose of 0.6 mg laquinimod would be greater than 0.6 mg (e.g., 0.64 mg) due to the presence of the additional salt ion.

As used herein, “about” in the context of a numerical value or range means i10% of the numerical value or range recited or claimed.

As used herein, a composition that is “free” of a chemical entity means that the composition contains, if at all, an amount of the chemical entity which cannot be avoided although the chemical entity is not part of the ation and was not affirmatively added during any part of the manufacturing process.

For example, a composition which is “free” of an alkalizing agent means that the alkalizing agent, if present at all, is a ty component of the composition by weight. Preferably, when a composition is “free” of a ent, the composition comprises less than 0.1 wt%, 0.05 wt%, 0.02 wt%, or 0.01 wt% of the component.

As used herein, “alkalizing agent” is used interchangeably with the term “alkaline-reacting component” or “alkaline agent” and refers to any pharmaceutically acceptable excipient which neutralizes protons in, and raises the pH of, the pharmaceutical composition in which it is used.

PCT/U52012/048689 As used herein, “oxidation reducing agent” refers to a group of als which includes an “antioxidant”, a “reduction agent” and a “chelating agent”.

As used herein, “antioxidant” refers to a compound selected from the group consisting of erol, methionine, glutathione, tocotn'enol, dimethyl glycine, betaine, butylated hydroxyanisole, butylated hydroxytoluene, turmerin, n E, ascorbyl ate, tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium or potassium metabisulfite, sodium or potassium sulfite, alpha tocopherol or derivatives thereof, sodium ascorbate, disodium edentate, BHA (butylated yanisole), a pharmaceutically acceptable salt or ester of the mentioned compounds, and mixtures thereof.

The term “antioxidant” as used herein also refers to Flavonoids such as those selected from the group of quercetin, morin, naringenin and hesperetin, taxifolin, n, quercitrin, myricitrin, ein, apigenin and biochanin A, flavone, ridol, isoflavonoids such as the soy isoflavonoid, genistein, catechins such as the tea catechin epigallocatechin gallate, flavonol, epicatechin, hesperetin, chrysin, diosmin, hesperidin, luteolin, and rutin.

As used herein, “reduction agent” refers to a compound selected from the group consisting of thiol— containing compound, thioglycerol, mercaptoethanol, thioglycol, thiodiglycol, ne, thioglucose, dithiothreitol (DTT), dithio-bis-maleimidoethane (DTME), 2,6-di-tert-butylmethylphenol (BHT), sodium dithionite, sodium bisulphite, idine sodium sulphite, and ammonium bisulphite." As used herein, “chelating agent” refers to a compound ed from the group consisting of penicillamine, trientine, N,N'—diethyldithiocarbamate (DDC), 2,3,2’—tetraamine (2,3,2'-tet), neocuproine, ,N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), l 1 0-phenanthroline , (PHE), tetraethylenepentamine, triethylenetetraamine and tris(2—carboxyethyl) phosphine , ferrioxamine, CP94, EDTA, deferoxainine B (DFO) as the methanesulfonate salt (also known as desferrioxanilne B mesylate (DFOM)), desferal from Novartis (previously Ciba-Giegy), and apoferritin.

As used herein, a pharmaceutical composition is “stable” when the composition preserves the physical stability/integrity andfor chemical stability/integrity of the active pharmaceutical ingredient during storage. Furthermore, “stable pharmaceutical composition” is characterized by its level of degradation products not exceeding 5% at 40°C/75%RH after 6 months or 3% at 55°C/75% RH after two weeks, compared to their level in time zero.

As used herein, “combination” means an lage of reagents for use in therapy either by aneous or contemporaneous administration. Simultaneous administration refers to administration of an admixture (Whether a true mixture, a suspension, an emulsion or other physical combination) of the laquinimod and the lFN-B. In this case, the ation may be the admixture or PCT/U82012/048689 separate containers of the laquinimod and the IFN—B that are combined just prior to administration.

Contemporaneous stration refers to the separate administration of the imod and the IFN— B at the same time, or at times sufficiently close together that a synergistic activity relative to the activity of either the laquinimod or the IFN-B alone is observed.

As used herein, “add—on” or “add—on therapy” means an assemblage of reagents for use in therapy, wherein the subject receiving the therapy begins a first treatment n of one or more reagents prior to beginning a second treatment regimen of one or more different reagents in addition to the first treatment regimen, so that not all of the reagents used in the therapy are started at the same time. For example, adding laquinimod therapy to a patient already receiving lFN—B therapy.

As used herein, “effective” when referring to an amount of laquinimod and/or interferon—beta (lFN-B) refers to the quantity of laquinimod and/or interferon—beta (lFN—B) that is sufficient to yield a desired therapeutic response t undue adverse side s (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this ion.

“Administering to the subject” or “administering to the (human) patient” means the giving of, dispensing of, or application of medicines, drugs, or remedies to a subject/patient to relieve, cure, or reduce the symptoms associated with a condition, e.g., a pathological condition.

“Treating” as used herein asses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., RMS, or ing, suppressing, inhibiting, reducing the severity of, eliminating or substantially eliminating, or ameliorating a symptom of the disease or disorder. “Treating” as applied to patients presenting CIS can mean delaying the onset of clinically definite multiple sclerosis (CDMS), delaying the progression to CDMS, reducing the risk of conversion to CDMS, or reducing the frequency of relapse in a patient who experienced a first clinical episode consistent with multiple sclerosis and who has a high risk of developing CDMS.

“Inhibition” of disease progression or disease complication in a subject means ting or reducing the e ssion and/or disease complication in the subject.

A “symptom” associated with RMS includes any clinical or laboratory manifestation associated with RMS and is not limited to what the t can feel or observe.

As used herein, “a subject afflicted with ing multiple sclerosis” means a subject who has been ally diagnosed to have relapsing multiple sclerosis (RMS) which includes ing-remitting multiple sclerosis (RRMS) and ary Progressive multiple sclerosis (SPMS).

As used herein, a t at “baseline” is as subject prior to stration of laquinimod. 2012/048689 A “patient at risk of developing MS” (i.e. clinically definite MS) as used herein is a patient presenting any of the known risk factors for MS. The known risk factors for MS include any one of a clinically isolated syndrome (CIS), a single attack suggestive of MS without a lesion, the presence of a lesion (in any of the CNS, PNS, or myelin sheath) without a clinical attack, nmental factors (geographical location, climate, diet, toxins, sunlight), genetics (variation of genes encoding HLA- DRBl, lpha and lLZR-alpha), and immunological ents (viral infection such as by Epstein-Barr virus, high avidity CD4+ T cells, CD8+ T cells, anti-NF-L, anti-CSF 114(Glc)).

“Clinically ed syndrome (CIS)” as used herein refers to l) a single clinical attack (used interchangeably herein with “first clinical event” and “first inating event”) suggestive of MS, which, for example, presents as an episode of optic neuritis, blurring of vision, diplopia, ntary rapid eye movement, blindness, loss of balance, tremors, ataxia, vertigo, clumsiness of a limb, lack of co—ordination, weakness of one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesia, burning sensations, muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of , slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, frequency, incomplete emptying and incontinence), bowel problems (including constipation and loss of bowel l), impotence, diminished sexual arousal, loss of sensation, ivity to heat, loss of short term memory, loss of concentration, or loss of judgment or reasoning, and 2) at least one lesion suggestive of MS. In a specific example, CIS diagnosis would be based on a single clinical attack and at least 2 lesions suggestive ofMS measuring 6 mm or more in er.

“Relapse Rate” is the number of ed es per unit time. lized relapse rate” is the mean value of the number of confirmed relapses of each patient multiplied by 365 and divided by the number of days that patient is on the study drug.

“Expanded lity Status Scale” or “EDSS” is a rating system that is ntly used for classifying and standardizing the condition of people with multiple sclerosis. The score ranges from 0.0 representing a normal neurological exam to 10.0 representing death due to MS. The score is based upon neurological testing and examination of functional systems (FS), which are areas of the central nervous system which l bodily functions. The functional systems are: Pyramidal (ability to walk), Cerebellar (coordination), Brain stem (speech and swallowing), Sensory (touch and pain), Bowel and bladder functions, , Mental, and Other (includes any other neurological findings due to MS) (Kurtzke IF, 1983).

A “confirmed progression” ofEDS S, or “confirmed disease progression” as measured by EDSS score is defined as a 1 point increase from baseline EDSS sustained for at least 3 months. In addition, confirmation of progression cannot be made during a relapse.

WO 2013016686 “Adverse event” or “AE” means any rd medical occurrence in a clinical trial subject administered a medicinal product and which does not have a causal relationship with the ent.

An adverse event can therefore be any unfavorable and unintended sign ing an abnormal laboratory finding, symptom, or diseases temporally associated with the use of an investigational medicinal product, whether or not considered related to the investigational medicinal product.

“Gd—enhancing lesion” refers to lesions that result from a breakdown of the brain barrier, which appear in st studies using gandolinium contrast agents. Gandolinium enhancement provides information as to the age of a , as Gd-enhancing lesions typically occur within a six week period of lesion formation.

“Magnetization Transfer Imaging” or “MTI” is based on the magnetization interaction (through dipolar and/or chemical exchange) between bulk water protons and macromolecular protons.

By applying an off resonance radio frequency pulse to the macromolecular protons, the saturation of these protons is then transferred to the bulk water protons. The result is a se in signal (the net magnetization of visible protons is reduced), depending on the magnitude of MT between tissue macromolecules and bulk water. “MT” or “Magnetization Transfer” refers to the transfer of longitudinal magnetization from the hydrogen nuclei of water that have restricted motion to the en nuclei of water that moves with many degrees of m. With MTI, the ce or absence of macromolecules (e.g. in membranes or brain tissue) can be seen (Mehta, 1996; Grossman, 1994).

“Magnetization Resonance Spectroscopy” or “MRS” is a specialized technique associated with ic resonance imaging (MRI). MRS is used to measure the levels of different metabolites in body tissues. The MR signal produces a spectrum of resonances that correspond to different molecular arrangements of the isotope being “excited”. This signature is used to diagnose certain metabolic disorders, especially those affecting the brain, (Rosen, 2007) as well as to provide information on tumor metabolism (Golder, 2007).

As used herein “mobility” refers to any ability relating to walking, walking speed, gait, strength of leg muscles, leg fianction and the ability to move with or without assistance. Mobility can be evaluated by one or more of several tests including but not limited to tion Index, Time 25 foot walk, Six- Minute Walk (6MW), Lower Extremity Manual Muscle Test ) and EDSS. Mobility can also be reported by the subject, for e by questionnaires, including but not limited to 12—Item Multiple Sclerosis Walking Scale (MSWS-12). Impaired Mobility refers to any ment, difficulty or disability relating to mobility.

“Tl-weighted MRI image” refers to an MR—image that emphasizes T1 contrast by which lesions may be ized. Abnormal areas in a Tl—weighted MRI image are “hypointense” and appear as dark spots. These spots are generally older lesions.

“T2-weighted MR] image” refers to an MR-image that emphasizes T2 st by which lesions may be ized. T2 lesions represent new inflammatory activity.

The “Six-Minute Walk (6MW) Test” is a commonly used test developed to assess exercise capacity in patients with COPD (Guyatt, 1985). It has been used also to measure mobility in multiple sclerosis patients (Clinical Trials Website).

The “Timed~25 Foot Walk” or “T25—FW” is a quantitative mobility and leg function performance test based on a timed 25—walk. The patient is directed to one end of a clearly marked 25—foot course and is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the ction to start and ends when the patient has d the 25—foot mark. The task is immediately administered again by having the patient walk back the same distance. Patients may use assistive devices when doing this task. The score for the T25-FW is the e of the two completed trials. This score can be used individually or used as part of the MSFC composite score (National MS Society Website).

One of the central symptoms of multiple sclerosis is fatigue. Fatigue can be measured by several tests including but not limited to decrease of French valid versions of the e Impact Scale (EMIF-SEP) score, and European Quality of Life (EuroQoL) Questionnaire (EQSD). Other tests, including but not limited to Clinician Global sion of Change (CGIC) and Subject Global sion (SGI), as well as EQ-SD, can be used to evaluate the general health status and quality of life ofMS patients.

“Ambulation Index” or “Al” is a rating scale developed by Hauser et al. to assess mobility by evaluating the time and degree of assistance required to walk 25 feet. Scores range from O (asymptomatic and fully active) to 10 (bedridden). The patient is asked to walk a marked 25-foot course as quickly and safely as possible. The examiner records the time and type of ance (e.g., cane, walker, crutches) needed. (Hauser, 1983) “EQ—SD” is a standardized questionnaire instrument for use as a measure of health outcome applicable to a range of health conditions and treatments. It provides a simple ptive profile and a single index value for health status that can be used in the al and economic evaluation of health care as well as tion health surveys. EQ—SD was developed by the “EuroQoL” Group which comprises a network of ational, multilingual, multidisciplinary researchers, originally from seven centers in England, Finland, the Netherlands, Norway and Sweden. The EQ-SD questionnaire is in the public domain and can be ed from EuroQoL.

W0 20131016686 PCT/U52012/048689 “SF-36” is a multi-purpose, short-form health survey with 36 ons which yields an 8-scale profile of onal health and well—being scores as well as psychometrically-based physical and mental health summary es and a preference—based health utility index. It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group. The survey is developed by and can be obtained from QualityMetric, Inc. of Providence, RI.

A “pharmaceutically acceptable carrier” refers to a carrier or excipient that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable /risk ratio. It can be a pharrnaceutically acceptable t, suspending agent or vehicle, for delivering the instant compounds to the subject.

It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also ed by the invention. For e, “0.1—2.5mg/day” includes 0.1 mg/day, 0.2 mg/day, 0.3 mg/day, etc. up to 2.5 mg/day.

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

Experimental s EXAMPLE 1: Assessment Of Add-on Effect Of Laguinimod In Mice Treated With Glatiramer Acetate gGA) Or Interferon-beta (IFN—fiz Mice were treated with a sub—optimal dose of imod (lOmg/kg) alone or add on glatiramer acetate (12.5mg/kg) or IFN-B 00 IU/mouse). In both cases, the combined treatment ed in improved efficacy when compared to each treatment alone.

EXAMPLE 2: Activity of interferon~|§ administered daily, subcutaneous (sc). alone or in combination with laguinimod in chronic EAE in C57 BI mice Experimental autoimmune alomyelitis (EAE) is an animal model y used with rodents) of the human CNS demyelinating diseases, including MS. MOG induced EAE in the C57Bl strain of mice was selected, as it is an established EAE model to test the efficacy of ate molecule for MS treatement.

In this experiment interferon-[3 is administered daily, subcutaneous (so). alone or in combination with laquinimod to chronic MOG induced EAE in C57 BI mice. Both were administered from the beginning ofthe study in the MOG induced EAE in C57Bl mice.

General Design Disease was induced in all mice by the ion of the encephalitogenic emulsion (MOG/CPA) and intraperitoneal injection of Pertussis toxin on the first day and 48 hours later. IFN-B at dose levels of 50,000 and 5000,000 IU/mouse was administered by the subcutaneous route, once daily (QD).

Laquinimod at dose levels of 10 and 25 mg/mouse was administered by the oral route, once daily (QD). Both IFN-B and laquinimod were administered prophylactic from disease induction — Day 1 until termination of the study. Two additional groups of IFN—B at dose level of 500,000 were treated either prophylactic (Day 1—7) or from onset (Day 8—18) to study activity of IFN—B in prophylactic and therapeutic .

Materials eron beta—la ) (Rebif®, 44ug/0.5m1/syringe, equivalent to 1.2 x 107 units (IU)/0.5ml/syringe), Laquinimod, PBS (Sigma), Pertussiis toxin (Sigma), MOG 35-55 (Mnf Novatide), te Freund’s Adjuvant (CFA) (Signma), Saline (Mnf—DEMO SA).

Healthy, nulliparous, non-pregnant female mice of the C57BL/6 strain were used in the study. The animals weighed 18—22 grams and were approximately 8 weeks old on receipt. The body weights of the animals were recorded on the day of delivery. Overtly healthy animals were assigned to study groups arbitrarily before treatment commenced.

Procedures EAE was induced by ing the ecephalitogenic mixture (emulsion) consisting of MOG (150.0ug/mouse) and CFA ning M. tuberculosis (1mg MG/mlCFA). A volume of 0.2 ml of encephalitogenic emulsion was injected aneously into the flanks of each mouse (Dose = 0.15 mg MOG and 0.2 mg MT/mouse) Pertussis toxin in 0.2 m1 dosage volume is injected intraperitonieally on the day of ion and 48 hours later (total amount is 0.2 ug/mouse; 100.0 ng/O.2ml/mouse).

The mice were allocated to the following treatment groups of 13 mice each.

Table 1: Experimental design Group f Treatment dose/day Administration Regimen Groups Route r (treatment ‘initiation L-AQUINIMQD 10 rug/kg 7: -LAQUTNIMOD 25mg/kg Oral, QD : LAQUTNIMOD from Day 1 -IFN-B ‘ 500000 SQQD to 30 daily & IFN—B from , , , ,, ,, . Day 1 to 18 daily LAQUINIMOD ‘ + Oral (QD) + IFNB sc (QD) LAQUINIMOD + Oral (QD) + : IFN[3 sc (QD) : ,,, ~ , SC,QD The mice were administered with the various concentrations of IFN—B (2.5 X106 and 2.5 X 105 IU/ml) at volume dose level of 200pl/mouse by subcutaneous route equivalent to 50,000 and 500,000 IU/mouse respectively.

The laquinimod ation was administered from Day 1, once daily (QD). Four hours interval was maintained between administration of laquinimod and lFN—B.

Experimental Observations All animals were ed once daily to detect if any are moribund. Mice were also d once weekly. Further, the mice were observed daily from the 8th day post—EAE induction and EAE clinical signs were scored. The scores were recorded on observation cards ing to the grades described in Table 2 below.

PCT/U82012/048689 Table 2: Evaluation of the EAE clinical signs ___-_ 3 Hind leg wobbly walk - when the mouse walks the hind legs are unsteady Hind leg paralysis The mouse drags its hind legs but is able to move around using its fore les The mouse can't move around, it looks thinner and emaciated.

Full paralysis All mice with score 1 and above were considered sick. When the first clinical sign appears all mice were given food soaked in water, which was spread on different places on the bedding of the cages.

For calculation es, the score of s that were sacrificed or died (6) was carried forward.

Interpretation ofResults Calculation of the incidence of disease gDisease ratio) . The number of sick animals in each group were summed. o The incidence of disease was calculated as N . k . . . t t d l 0 INCIDENCE of DISEASE =[W ] No. of sick mice in control group . The percent inhibition according to incidence was calculated as “mber of “Ck ””06 m d group ] INHIBITION (%)of INCIDENCE = £1——————————————-———-—-—-————N x100 Number of Sick mice in control group W0 2013l016686 PCT/U52012/048689 ation of the mortalig/moribundig rate (mortalig ratio) . The number of dead or nd s in each group were summed.

. The mortality of disease was calculated as dead or morzbound mzcezn treated group ] MORTALITY of DISEASE = [No.of No.0f dead or moribound mice in control group - The percent inhibition according to mortality was calculated as Number of dead or mortbound treated group ] INHIBITION (%) of MORTALITY __ (1 x100 Number of dead or moribound mice in control group Calculation of duration of disease . The mean duration ofdisease expressed in days was calculated as )3 Duration 0f disease 0f each mouse Mean Duration = ( No.0f mice in th e group 1 0 Calculation of mean delay in onset of disease . The mean onset of disease expressed in days was calculated as Onset of disease of each mouse] Mean Onset = [E No.0f mice in th e group . The mean delay in onset of disease expressed in days was calculated by subtracting the mean onset of disease in control group from test group. 1 5 Calculation of the mean maximal score and percent inhibition . The mean maximal score (MMS) of each group was calculated as Score of ea ch mouse) [MMS _ (EMaximal N0. of mice in th e group . The percent tion ing to MMS was calculated as Mu z~ r d INHIBITION (%) of MMS =(PM) x 100 MMS of control group Calculation of the group mean score and percent inhibition . The daily scores of each mouse in the test group were summed and the individual mean daily score (IMS) was ated as 2 Body score of mouse [MS =[ Observation period (days)J . The mean group score (GMS) was calculated as EIMS of ea chmouse GMS =[ No. of mice in th e group ] . The percent inhibition was calculated as M t d INHIBITION (%) of GMS = l—W x100 GMS of control group Results/Discussion A summary of the incidence, mortality, mean maximal scores (MMS), group mean score (GMS), duration of the disease, onset of the disease and the activity of each group compared to the e treated control group is shown in Table 3 below.

WO 16686 PCT/U82012/048689 Table 3: Mortality, incidence, MMS, GMS, Duration and Onset and EAE inhibition compared to Vehicle InnMortalityIncidence % MMS % GMS % Mean Onset Mean 1 2 I .

Negative 0/13 13/13 3.2 j; .0 10.5 i 18.1 1’.

Control 1.0 + 1.3 4.63 Vehicle 10 1.0 Laquinimod 0/13 8/13 38.5 % 1.8 i , 3.8 % 0.8 60.0 % 21.3 _+_ 9.2 i mg/kg 1.7 p= 0.04 + p = 0.003 8.2 8.3 I i " I a " Laquiniomd 0/15 5/15o1.5 % 75.0 % 0.3 85.0%p=<0.001 25.7 i 7.8 5.0 35 mg/kg 0.8 i p + 0.5 p = < 7.4 I II I M a - IFN-B 0/13 11/13 15.4 % 2.6 i . 1.7 . 15.4 i 50,000 1.4 + . p = 0.3 7.8 lU/mouse lFN-B 0/13 12/13 7.7 % 500,000 IU/mouse Laquinimod + 0/13 113 IFN-B mg/kg + 50,000 IU/mouse Laquinimod + 0/15 5/15 IFN-B mg/kg + 500,000 lU/mouse lFN-B (Day 1 0/13 13/13 to 7) 500,000 IU/mouse IFN-B (Day8 0/13 10/13 to 30) 500,000 IU/mouse WO 16686 PCT/U82012/048689 The activity of the IFN-B administered groups in combination with laquinimod (10 mg/kg) compared to the group d with laquinimod (10 mg/kg) is shown in Table 4 below.

Table 4: Laquinimod alone and in combination with IFN-B compared to laquinimod (10 mg/kg).

Mortalit Incidenc % Mean Treatme y inhibitio inhibitio 3 Duratio nt n2 n (daYS) Laquinmod 0113 . mg/kg .OH‘Q Laquinmod 0/15 mg/kg 151+? Laquinmod m3 + IFN-B mg/kg + .0”? 50,000 IU/mouse Laquinmod #15 + lFN-B mg/kg + 500,000 The activity as compared to vehicle and laquinimod are shown in Tables 5 and 6 below: Table 5: Activity compared to vehicle —-_-:I m—_— -_—_ Table 6: Activity compared to Laquinimod —GrouMean Score GMS Vehicle (saline —_ La uinimod 10m - __ La uinimod 25m - IFN beta 50,000 IU/mouse) IFN beta 500,0001U/m0use__ Table 7: ty compared to interferon-B (500,000 TU/mouse) upMean Score . .

IFN beta 500,000 IU/mouse) _- Lauinimod 25 m-/k 0 3 66.7% IFN beta 50,000 IU/mouse) + La uinimod l0 m k ) ——0.5 IFN beta (500,000 IU/mouse + Lauinimod (10 m k ) IFN beta 00 IU/mouse _ Under the conditions of the test IFN-B at dose levels of 50,000 IU/mouse and 500,000 IU/mouse exhibited additive activity in the suppression of EAE when tested in combination with laquinimod at dose level of 10 mg/kg.

The groups d with IFN—l3 at dose levels of 50,000 IU/mouse and 500,000 lU/mouse in combination with laquinimod (10 mg/kg) exhibited 75% and 90% activity respectively according to GMS compared to 15%, 55% and 60% activity in groups treated with IFN—[5 at dose levels of 50,000 IU/mouse and 500,000 IU/mouse and laquinimod at dose level of 10 mg/kg respectively when compared to the vehicle administered control group.

The groups treated with IFN~B at dose levels of 50,000 se and 500,000 IU/mouse in combination with laquinimod (10 mg/kg) exhibited 37.5% and 75% ty respectively according to GMS when compared to group treated with laquinimod at dose level of 10 mg/kg.

It is ant to note the mouse dosing ted here cannot be used to determine human dosing by simply adjusting for body weight, because a gram ofmouse tissue is not equivalent to a gram of human tissue. For this reason, the National Institutes of Health (NIH) es a table of Equivalent Surface Area Dosage Conversion Factors below (Table 8) which provides conversion factors that account for surface area to weight ratios between species.

Table 8: lent Surface Area Dosage Conversion Factors .Mouse 20 g Rat 150g Monkey 3kg Dog 8kg Man 60kg FROM 1/4 1/6 1/12 1 3/5 Dog --4 1 12 12/3 ——-7 3 EXAMPLE 3: Clinical Trial Phase II — Assessment Of Add—on Effect Of La uinimod In Rela sin Multi le Sclerosis RMS Sub‘ects d With Glatiramer Acetate GA Or Interferon-beta IFN— A multinational, multicenter, randomized, double—blind, el—group, placebo—controlled study, followed by a double—blind active extension phase is conducted to assess the safety, tolerability and efficacy of two daily doses of oral laquinimod (0.6mg or 1.2mg) in adjunct to glatiramer acetate (GA) or interferon-beta (IFN- B)-la/ lb preparations in subjects with relapsing multiple sclerosis (RMS).

Study Duration The total study duration for each le subject will be up to 19 months: 0 Screening phase: up to about 1 month. 0 Double-Blind Placebo Controlled (DBPC) ent phase: about 9 months of once—daily oral administration of laquinimod 0.6 , day or placebo in addition to current therapy (i.e., subcutaneous GA 20mg or any of the following lFN—fi preparations: ® Avonex Betaseron®/Betaferon®, Rebif® or Extavia®). o Double-Blind Active Extension (DBAE) phase: all subjects who complete all 9 months of the DBPC treatment phase are offered the opportunity to continue to a DBAE phase. During this phase, all subjects continue the same background injectable treatment which they used in the DBPC phase. 0 Subjects who were originally assigned to either of the active oral treatment arms nimod 0.6 mg or 1.2 mg) continue with their original oral treatment assignment. Subjects originally PCT/U82012/048689 assigned to placebo are equally randomized to either laquinimod 0.6mg or 1.2mg. The duration of this phase is 9 months.

Study tion Relapsing Multiple Sclerosis (RMS).

Study Design Eligible subjects are equally (121:1) randomized into one of the following treatment arms: 1. GA 20 mg or any IFN—B preparation + oral daily administration of laquinimod capsules 0.6 2. GA 20 mg or any IFN-B preparation + oral daily administration of laquinimod capsules 1.2 mg. 3. GA 20 mg or any IFN-B preparation + oral daily o .

The 0.6 mg laquinimod capsule can be manufactured according to the method disclosed in PCT International Application Publication No. 7/ 146248, published December 21, 2007 (see, page , line 5 to page 11, line 3).

Randomization is stratified in a way that in each arm the number of subjects treated by GA will be equal to the number of subjects treated by IFN-B preparations (Avonex®, ron®/Betaferon®, Rebit® or Extavia®).

During the DBAE phase, subjects ue the same background injectable treatment which they used in the DBPC phase. ts who were originally ed to either of the active oral arms [either laquinimod 0.6mg (arm I) or l.2mg (arm 2)] continue with their original oral treatment assignment.

Subjects originally assigned to placebo (arm 3) are equally ized to either laquinimod 0.6mg or 1.2mg.

During the DBPC phase, subjects are evaluated at study sites for ll scheduled visits at Months: —1 (screening), 0 (baseline) and every month thereafter until Month 9 (termination! early termination).

During the DBAE phase subjects are evaluated at study sites for 6 scheduled visits at months 9 [Baseline EXT; the termination visit of the DBPC phase], 10/ lAE, 11/2AE, 12/3AE, 15/4AE and 18/5AE (termination/ early termination visit of the DBAE phase).

The following assessments are med at the specified time points: WO 2013016686 2012/048689 During both DBPC and DBAE phases, vital signs are measured at each study visit.

During the DBPC phase, a physical examination is performed at Month —1 (Screening) and Months 0 (Baseline), 1, 3, 6 and 9 (Termination/Early Termination visit of the DBPC phase).

During the DBAE phase, a physical examination is performed at Month 9 (Baseline EXT; termination visit of the DBPC , lO/lAE, 12/3AE and 18/5AE (Termination/Early Termination visit of the DBAE .

The following safety clinical laboratory tests are performed: a. Complete blood count (CBC) with differential — at all scheduled visits in both DBPC and DBAE phases. b. Serum chemistry (including electrolytes, liver enzymes, creatinine, direct and total bilirubin and pancreatic amylase), and urinalysis is performed at all led visits in both DBPC and DBAE phases. Lipase is tested in case of abnormal pancreatic amylase results. Glomerular ion rate (GFR) is calculated at Month -1 (Screening) and prior to each MRI scan. c. Lipid profile (total cholesterol, HDL, LDL and triglycerides) is performed at month ~ 1 (Screening) or Month 0 (Baseline) of the DBPC phase, under fasting conditions. d. During the DBPC phase, d on tests (TSH, T3 and free T4) are performed at Months 0 (Baseline), 6 and 9 (Termination/ Early termination visit of the DBPC phase). During the DBAE phase d function tests (TSH, T3 and free T4) are performed at Months 9 (Baseline EXT; termination visit of the DBPC phase), /4AE and 18/5AE (termination/ early termination visit of the DBAE phase). e. Urinalysis is performed at the Screening visit. f. Serum B—hCG (human choriogonadotropin beta) is performed in women of child- bearing potential at each scheduled study visit in both DBPC and DBAE phases.

Urine dipstick B—hCG in women of child—bearing potential during both the DBPC and the DBAE phases, at all post-Screening study visits and the early termination visit. In addition, during the DBAE Phase, urine B-hCG test is performed at home twice between scheduled visits: a. At months 13AE and 14AE (30i4 days and 60i4 after Month 12AE visit, respectively).

W0 2013.1016686 PCTfU82012/048689 b. At months 16AE and 17AE (30:84 days and 60i4 after Month 15AE visit, respectively).

The subject is contacted by the site staff via telephone within 72 hours after the test is led to be performed and asked specific questions regarding the test. In case of suspected pregnancy (positive urine B—hCG test result), the caller instructs the subject to stop taking the study drug and to arrive to the site as soon as possible (but within 10 days) with all study drugs.

During the DBPC phase, electrocardiograms (ECG) is performed at months —1 (screening), 0 ine; three recordings 10 min apart, before first dose), 1, 2, 3, 6 and 9 (termination/early termination visit of the DBPC phase). During the DBAE phase, ECGs are med at Months 9 (Baseline EXT; ation visit of the DBPC phase), 10/lAE, ll/2AE, 12/3AE, /4AE and 18/5AE (Termination/ Early Termination visit of the DBAE phase).

Chest X—ray is performed at month —1 (screening), if not performed within 6 months prior to the screening visit.

Adverse Events (AEs) are monitored hout the study.

Concomitant Medications are monitored throughout the study (both phases).

During the DBPC phase, neurological evaluations, ing Expanded Disability Status Scale (EDSS), Ambulation Index (Al) and onal system score (F8) are performed at Months: —1 (screening), 0 (baseline), 3, 6, and 9 (Termination/Early Termination of the DBPC phase). During the DBAE phase, neurological evaluations, including EDSS, Al and FS scores are performed at Months 9 (Baseline; ation visit of the DBPC phase), 12/3AE, 15/4AE and lS/SAE (Termination/Early Termination of the DBAE phase).

. During the DBPC phase, Symbol Digit Modalities Test (SDMT) are performed at Months 0 (Baseline), 6 and 9 (Termination/Early Termination visit of the DBPC phase). During the DBAE phase, SDMT is performed at Months 9 (Baseline EXT; ation visit of the DBPC phase), 15/4AE and lS/SAE nation/Early Termination visit of the DBAE phase). 11. During the DBPC phase, each subject undergoes 3 MRI scans at Months: 0 (baseline), 3 and 9 (Termination/Early Termination Visit of the DBPC phase). During the DBAE phase, each 3O subject undergoes 2 MRI scans at Months 9 (Baseline EXT; Termination visit scan of the DBPC phase) and 18/5AE (Termination/Early Termination Visit of the DBAE phase).

PCT/U82012/048689 12. During the DBPC phase, Pharmacokinetic (PK) study: Blood samples for analysis of laquinimod plasma concentrations are ted from all subjects at Months I, 3 and 6. 13. During the DBPC phase, whole blood samples are collected for lymphocyte immunophenotyping at Months 0 (Baseline), 3 and 9 (Termination/Early Termination). 14. Health Economics and Quality of Life: During the DBPC phase, the Work tivity and Activities Impairment Questionnaire-General Health GH) (US sites only) and the European Quality of Life (EuroQoL) Questionnaire (EQSD) are filled out at months 0 (Baseline), and 9 (Termination/Early Termination). During the DBAE phase, the WPAI-GH (US sites only) and the EQSD questionnaire are filled out at Months 9 (Baseline EXT; Termination Visit of the DBPC phase) and l8/5AE (termination/early termination visit of the DBAE phase).

. Relapses are confirmed/monitored throughout the study (both phases).

Relapse Treatment The allowed ent for a e is intravenous Methylprednisolone lgr/day for up to 5 consecutive days.

Monitoring The subjects are closely monitored through the study course by an external independent Data Monitoring Committee (DMC).

MRI Activity Alert Criteria 2O In case 5 or more GdE—Tl lesions are demonstrated on an MRI scan, the MRI reading center issues a notification letter to the Sponsor, investigator and the DMC. MRI parameters of activity are not considered stopping rules and the decision regarding individual subject‘s participation in the trial is at the tion of the treating physician.

Ancillag studies: Pharmacogenetic (PGx) assessment: Blood samples for PGx ters are collected from all subjects that signed the informed consent form (separate from that of the core study), pending Ethics Committees al, during the DBPC phase, ably at Month 0 (Baseline) or any other visit following Month 0.

Number ects Approximately 600 subjects.

Inclusion/Exclusion Criteria Inclusion Criteria 1. ts must have a documented MS diagnosis as defined by the Revised McDonald criteria [Ann Neurol 201 l: 69:292—302], with a relapsing disease course.

Subjects must be relapse free, in a stable neurological condition and free of corticosteroid treatment [intravenous (IV), intramuscular (1M) and/or oral] 60 days prior to randomization.

Subjects must be treated with GA (Copaxone®) or an IFN—B preparation (Avonex®, Betaseron®/Betaferon®, Rebit® or Extavia®), at a stable dose for at least 6 months prior to ization (switching between IFN—B preparations during the 6 months prior to randomization is allowed; switching between any lFN—B preparation and GA, or vice versa, is exclusionary), and there is no plan to change the subject’s injectable treatment (either Copaxone® or IFN-B preparation) during the course of the study.

Subjects must have an EDSS score of 1.5-4.5 (inclusive) at randomization.

Subjects must be between 18 and 55 years of age, inclusive.

Women of child—bearing potential must practice an acceptable method of birth control.

Acceptable methods of birth l in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, 2O partner’s omy or double—barrier method (condom or diaphragm with spermicide).

Subjects must be able to sign and date a written informed t prior to ng the study.

Subjects must be g and able to comply with the protocol requirements for the duration of the study.

Exclusion Criteria Have a non-relapsing, progressive form of MS (e.g., PPMS) (as defined by Lublin and Reingold, 1996).

An onset of a e, unstable neurological condition or any treatment with corticosteroids [intravenous (iv), intramuscular (im) and/or per os (po)] or corticotropic hormone 6O PCT/U52012/048689 days prior to randomization (last day of steroid treatment should be equal or greater than 60 days prior to ization). 3. Use of mental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to randomization. 4. Use ofimmunosuppressive agents within 6 months prior to randomization.

. Use of zumab (Tysabri®), fingolimod (Gilenya®) or anti—B cell therapy within the 2 years prior to ization. 6. Previous use of any of the following: cytotoxic agents, Mitoxantrone (Novantrone®), cladribine, laquinimod, total body irradiation, total lymphoid irradiation, stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation. 7. Previous treatment with intravenous immunoglobulin (IVIG) or plasmapheresis within 2 months prior to ization. 8. Use of moderate/strong inhibitors of CYP3A4 within 2 weeks prior to the randomization 9. Use of inducers of CYP3A4 within 2 weeks prior to randomization. 10. Pregnancy or breastfeeding. ll. A ZZXULN serum elevation of either alanine transaminase (ALT) or ate minase (AST) at screening. 12. Serum direct bilirubin which is EZXULN at ing 13. Subjects with a potentially clinically significant or unstable medical or surgical condition that 2O would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests or chest X—ray. Such conditions may include: a. A cardi0vascular or pulmonary disorder that cannot be well—controlled by standard treatment permitted by the study protocol. b. Renal es. c. Any form of acute or chronic liver disease. d. Known human immunodeficiency virus (HIV) positive status.

WO 2013016686 PCT/U52012/048689 e. A y of drug and/or alcohol abuse. f. An unstable psychiatric disorder. g. Any malignancies, excluding basal cell carcinoma (BCC), in the last 5 years. 14. A glomerular filtration rate (GFR) less than 60 ml/min at screening visit.

. A known history of sensitivity to gadolinium (Gd). 16. Inability to successfully undergo MRI seaming. 17. Previous endovascular ent for Chronic Cerebrospinal Venous Insufficiency (CCSVl). l8. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.

Route and Dosage Form 1. GA 20 mg or an preparation of interferon-beta (lFN—B) + oral daily administration of laquinimod capsules 0.6 mg (one laquinimod capsule 0.6 mg and one placebo capsule for laquinimod) (applicable to both DBPC and 'DBAE phases). 2. GA 20 mg/lmL or an IFN-B preparation + oral daily administration of imod 1.2 mg (2 capsules of laquinimod 0.6 mg) (applicable to both DBPC and DBAE phases) 3. GA 20 mg or an preparation of lFN-B + oral daily administration of placebo (2 placebo capsules for laquinimod) (applicable only to DBPC phase).

Outcome Measures The y objectives of the study are to assess the , tolerability and efficacy of two daily 2O doses of oral laquinimod (0.6mg or 1.2mg) in adjunct to GA or IFN-B preparation (Avonex®, ron®/Betaferon®, Rebif® or Extavia®) in subjects with RMS.

Primam Efficacy Endpoint for DBPC Phase: 0 The percent brain volume change (PBVC) between month 0 ine) to Month 9 (Termination/Early Termination after Month 6 of the DBPC phase).

WO 16686 PCT/U82012/048689 Key Exploratog Efficacy Endpoints for DBPC phase: Change in whole brain Magnetic Transfer Ratio (MTR) histogram between month 0 (Baseline) and Month 9 (Termination/Early Termination visit after Month 6 of the DBPC phase).

Time to Confirmed Disease Progression (CDP). CDP is defined as a sustained se in EDSS of 21 point from Baseline for at least 3 months. Progression cannot be confirmed during a relapse.

Exploratory nts for DBPC Phase The percent change in cortical thickness between month 0 (baseline) and month 9 (termination/early termination visit after month 6).

The cumulative number new Tl hypointense lesions at months 3 and 9 (termination/early termination visit after month 6).

The number of active (new T2 or GdE-Tl) lesions at month 3 that evolved into black holes at month 9 (termination/early ation visit after month 6).

The cumulative number of GdE—Tl lesions at months 3 and 9 (termination/early termination visit after month 6).

Change in T2 lesion volume from O (baseline) to month 9 (termination/early termination visit after month 6).

Change in GdE—Tl lesions volume from month 0 ine) to month 9 (termination/early 2O termination visit after month 6).

Change from baseline to month 9 (termination/early termination visit after month 6) in SDMT score.

The general health status, as assessed by the EuroQoL (EQSD) questionnaire.

Assessment of the effect of general health and symptom severity on work, using the work productivity and activities impairment l Health (WPAl-GH) questionnaire.

Annualized Relapse Rate (ARR).

The time to the first confirmed relapse.

WO 2013016686 PCT/U82012/048689 - Pharmacokinetics of laquinimod.

Exploratory Endpoints for DBAE Phase A similar set of endpoints are analyzed for the DBAE phase.

Safety and Tolerabilig Endpoints for DPBC phase 0 The cumulative number of GdE—Tl lesions at months 3 and 9. 0 The cumulative number of Combined Unique Active (CUA) lesions at months 3 and 9. 0 Number of subjects with adverse events. 0 Number of subjects with potentially clinically significant abnormalities based on laboratory tests and vital signs and ECGs during the study. 0 Proportion of subjects (%) who urely discontinue from the study, reason of discontinuation and the time to withdrawal. 0 Proportion of subjects (%) who urely tinue from the study due to adverse events (ABS) and the time to withdrawal.

Results/Discussion This study assesses safety, bility and efficacy of laquinimod in adjunct to glatiramer acetate (GA) or interferon—beta (IFN—B) in relapsing multiple sclerosis (RMS) subjects. Since the mechanisms of action of laquinimod and IFN-B have not been fully elucidated, the effect of the combined y cannot be predicted and must be evaluated mentally.

Daily administration of laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) as an add-on therapy for a patient already receiving interferon-beta (IFN—B) provides increased efficacy (provides an additive effect or more than an additive effect) in relapsing multiple sclerosis (RMS) subjects without unduly increasing adverse side effects or affecting the safety of the treatment. Daily administration of laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) as an add-on therapy to IFN-B is also safe for use in treating relapsing le sis (RMS) patients.

Administration of laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) as an add-on y to IFN—B provides a clinically meaningful advantage and is more effective (provides an additive effect or more than an additive ) in treating relapsing multiple sclerosis (RMS) ts than when lFN—B is administered alone (at the same dose) in the following manner: W0 2013IOI6686 1. The add-on therapy is more effective (provides an additive effect or more than an additive effect) in ng the decrease in brain volume (determined by the percent brain volume change (PBVC)), in relapsing multiple sclerosis (RMS) patients.

The add-on therapy is more effective (provides an additive effect or more than an additive effect) in increasing the time to confirmed e progression (CDP), in relapsing multiple sclerosis (RMS) ts, where CDP is defined as a sustained increase in EDSS of 21 point from Baseline for at least 3 . Progression cannot be confirmed during a relapse.

The add-on therapy is more ive (provides an additive effect or more than an additive effect) in reducing abnormalities observed in whole Brain MTR histogram, in relapsing multiple sclerosis (RMS) ts during.

The add-on therapy is more ive (provides an additive effect or more than an additive effect) in ng the number of confirmed relapses and therefore the relapse rate, in relapsing multiple sclerosis (RMS) patients.

The add—on therapy is also more effective (provides an additive effect or more than an additive effect) in reducing the accumulation of physical disability in relapsing multiple sclerosis (RMS) patients, as measured by the time to confirmed progression of EDSS.

The add-on therapy is more ive (provides an additive effect or more than an additive effect) in reducing nitored disease activity in relapsing multiple sclerosis (RMS) patients, as measured by the cumulative number of T1 Gd-enhancing lesions on Tl-weighted images, the cumulative number new Tl hypointense lesions, the cumulative number ofnew T2 lesions, the cumulative number of new Tl hypointense s on Tl-weight images (black holes), the number of active (new T2 or ) lesions, presence or absence of GdE lesions, change in total volume of Tl Gd-enhancing lesions, change in total volume of T2 lesions, and/or cortical thickness.

The add—on therapy is more ive (provides an additive effect or more than an additive effect) in reducing brain atrophy in relapsing le sclerosis (RMS) patients.

The add—on therapy is more effective (provides an additive effect or more than an additive effect) in reducing the frequency of relapses, the frequency of clinical exacerbation, and the risk for confirmed progression in relapsing multiple sis (RMS) patients.

WO 16686 PCT/U52012/048689 9. The add-on therapy is more effective (provides an additive effect or more than an ve effect) in increasing the time to confirmed relapse in relapsing multiple sclerosis (RMS) patients.

. The add-on therapy is more ive (provides an additive effect or more than an additive effect) in improving the l health status (as assessed by the EuroQoL (EQSD) questionnaire), symptom severity on work (as assessed by the work productivity and activities impairment General Health (WPAI-GH) questionnaire) and quality of life, in relapsing multiple sis (RMS) patients. 11. The add-on therapy is more effective (provides an additive effect or more than an additive effect) in decreasing cerebral dysfunction/cognitive impairment (as assessed by Symbol Digit Modalities Test (SDMT)), in relapsing multiple sclerosis (RMS) patients during the double blind study .

Administration of laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) as an add—on therapy to IFN—B provides a clinically meaningful advantage and is more effective (provides an additive effect or more than an additive effect) in delaying the conversion to clinically definite MS in patients presenting a C18 tive ofMS than when IFN—B is administered alone (at the same dose).

Administration of laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) as an add-on therapy to IFN-B provides a clinically meaningful advantage and is more effective (provides an additive effect or more than an additive effect) in reducing the rate of development of clinically definite MS, the occurrence of new MRI—detected lesions in the brain, the accumulation of lesion area in the brain and brain atrophy in persons at high risk for developing MS, and is more effective in reducing the ence of clinically definite MS and preventing rsible brain damage in these persons than when IFN—B is administered alone (at the same dose).

Based on the foregoing, analogous s are expected for therapy using laquinimod (p.o., 0.6 mg/day and 1.2 ) in combination with IFN—B. Specifically, daily administration of laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) in combination with IFN-B provides increased efficacy (provides an additive effect or more than an ve effect) over the administration of each agent alone in relapsing multiple sis (RMS) subjects without unduly increasing adverse side effects or affecting the safety of the ent. Daily administration of imod (p.o., 0.6 mg/day) in ation with interferon-beta (IFN-B) is also safe for use in treating relapsing multiple sclerosis (RMS) patients.

Administration of laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) in combination with IFN—B provides a clinically meaningful advantage and is more effective (provides an additive effect or more than an PCT/U52012/048689 additive effect) in treating relapsing multiple sclerosis (RMS) patients than when IFN—B is administered alone (at the same dose) in the following manner: 12. The combination therapy is more effective des an additive effect or more than an additive effect) in reducing the se in brain volume (determined by the percent brain volume change (PBVC)), in relapsing multiple sclerosis (RMS) patients. l3. The combination therapy is more effective (provides an additive effect or more than an additive effect) in increasing the time to confirmed disease progression (CDP), in relapsing multiple sclerosis (RMS) patients, where CDP is defined as a sustained increase in EDSS of 21 point from Baseline for at least 3 months. Progression cannot be ed during a relapse. 14. The ation therapy is more effective (provides an additive effect or more than an additive effect) in reducing abnormalities observed in whole Brain MTR histogram, in relapsing multiple sclerosis (RMS) ts during.

. The combination therapy is more effective (provides an additive effect or more than an ve effect) in reducing the number of confirmed relapses and therefore the relapse rate, in relapsing multiple sclerosis (RMS) patients. l6. The combination therapy is also more effective (provides an additive effect or more than an additive effect) in reducing the accumulation of physical disability in relapsing multiple sis (RMS) patients, as measured by the time to confirmed progression . 2O l7. The combination therapy is more effective (provides an additive effect or more than an additive ) in reducing MRI-monitored disease activity in relapsing multiple sclerosis (RMS) patients, as measured by the cumulative number of T1 (Ed—enhancing lesions on T1- weighted images, the cumulative number new Tl hypointense lesions, the cumulative number of new T2 lesions, the cumulative number ofnew Tl tense lesions on Tl-weight images (black holes), the number of active (new T2 or GdE—Tl) s, presence or e of GdE lesions, change in total volume of Tl Gd-enhancing lesions, change in total volume of T2 lesions, and/or cortical thickness. 18. The combination y is more effective (provides an additive effect or more than an additive effect) in reducing brain atrophy in relapsing multiple sclerosis (RMS) patients.

W0 ‘016686 PCT/U82012/048689 19. The combination therapy is more effective (provides an additive effect or more than an additive effect) in reducing the frequency of relapses, the frequency of clinical exacerbation, and the risk for confirmed progression in relapsing multiple sclerosis (RMS) patients.

. The combination therapy is more effective (provides an additive effect or more than an additive effect) in increasing the time to confirmed relapse in relapsing multiple sclerosis (RMS) patients. 21. The combination therapy is more effective (provides an ve effect or more than an additive effect) in improving the l health status (as assessed by the EuroQoL (EQSD) questionnaire), symptom severity on work (as assessed by the work productivity and activities impairment General Health (WPAI—GH) questionnaire) and quality of life, in relapsing multiple sclerosis (RMS) patients. 22. The ation therapy is more effective (provides an additive effect or more than an additive effect) in decreasing cerebral dysfunction/cognitive ment (as assessed by Symbol Digit Modalities Test (SDMT)), in relapsing multiple sclerosis (RMS) patients during the double blind study period.

Administration of laquinimod (p.o., 0.6 mg/day and 1.2 mg/day) in combination with IFN-B provides a clinically meaningful age and is more effective (provides an additive effect or more than an additive effect) in delaying the conversion to clinically definite MS in patients presenting a C18 suggestive ofMS than when IFN—B is administered alone (at the same dose).

Administration of laquinimod (p.0., 0.6 mg/day and 1.2 mg/day) in ation with IFN—B es a ally meaningful advantage and is more effective (provides an additive effect or more than an additive effect) in ng the rate of development of clinically definite MS, the occurrence of new tected lesions in the brain, the accumulation of lesion area in the brain and brain atrophy in persons at high risk for developing MS, and is more effective in reducing the occurrence of clinically definite MS and preventing irreversible brain damage in these persons than when IFN—B is administered alone (at the same dose).

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Claims (53)

What is claimed is:

1. Use of 0.6mg laquinimod in the cture of a medicament for the treatment of a human patient afflicted with multiple sclerosis or ting a clinically isolated syndrome, wherein the medicament is prepared as an add-on therapy to or in combination with an amount of interferon- 8, n the amounts when taken together is more effective to treat the human patient than when each agent at the same amount is administered alone.

2. Use of 0.6mg laquinimod and an amount of interferon-6 in the manufacture of a medicament for the treatment of a human patient afflicted with multiple sclerosis or presenting a clinically isolated me, wherein the amounts when taken together is more effective to treat the human patient than when each agent at the same amount is administered alone.

3. Use of an amount of laquinimod in the manufacture of a medicament for the treatment of a human patient afflicted with multiple sclerosis or presenting a clinically isolated syndrome, wherein the medicament is prepared as an add-on therapy to or in combination with an amount of interferon-6 (IFN-B), wherein the s when taken together are more effective to treat the human patient than when each agent at the same amount is administered alone.

4. Use of an amount of laquinimod and an amount of interferon-6 in the cture of a medicament for the ent of a human t afflicted with multiple sclerosis or presenting a clinically isolated syndrome, n the amounts when taken together are more effective to treat the human patient than when each agent at the same amount is administered alone.

5. The use of any one of claims 1—4, wherein the laquinimod is laquinimod sodium.

6. The use of any one of claims 1—5, n the multiple sclerosis is relapsing multiple sclerosis.

7. The use of any one of claims 1—6, wherein the multiple sclerosis is ing—remitting multiple sclerosis.

8. The use of any one of claims 1-7, wherein the amount of laquinimod and the amount of interferon-B when taken together is effective to reduce a symptom of multiple sclerosis in the human patient.

9. The use of claim 8, wherein the symptom is a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of al lity, frequency of relapses, decreased time to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerbation, brain y, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, deterioration of visual on, fatigue, impaired mobility, cognitive impairment, reduction of brain , abnormalities observed in whole Brain MTR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work.

10. The use of claim 9, n the amount of laquinimod and the amount of interferon-B when taken together is effective to decrease or inhibit reduction ofbrain .

11. The use of claim 10, wherein brain volume is measured by percent brain volume change (PBVC).

12. The use of claim 9, wherein the amount of laquinimod and the amount of eron-B when taken together is effective to increase time to confirmed disease ssion.

13. The use of claim 12, n time to confirm disease progression is increased by 20-60%, or by at least 50%.

14. The use of claim 9, wherein the amount of laquinimod and the amount of interferon—B when taken together is effective to decrease abnormalities observed in whole brain MTR histogram.

15. The use of claim 9, wherein the accumulation of physical disability is measured by Kurtzke Expanded Disability Status Scale (EDSS) score, and /or wherein the accumulation of physical disability is assessed by the time to confirmed disease progression as measured by Kurtzke Expanded Disability Status Scale (EDSS) score.

16. The use of claim 15, n the patient had an EDSS score of 0-5 .5, an EDSS score of 1.5- 4.5, or an EDSS score of 5.5 or greater prior to administration of laquinimod and/or confirmed disease progression is a 1 point increase of the EDSS score or 0.5 point increase of the EDSS score.

17. The use of claim 9, wherein impaired mobility is assessed by the 25 Foot Walk test, the 12-Item Multiple Sclerosis Walking Scale (MSWS—lZ) self-report questionnaire, the Ambulation Index (AI), the Six—Minute Walk (6MW) Test, or the Lower Extremity Manual Muscle Test ) Test.

l8. The use of claim 9, wherein the amount of laquinimod and the amount of interferon-B when taken together is effective to reduce cognitive impairment.

l9. The use of claim 18, wherein cognitive impairment is assessed by the Symbol Digit Modalities Test (SDMT) score.

20. The use of claim 9, wherein general health status is assessed by the EuroQol (EQSD) onnaire, Subject Global Impression (SGI), or Clinician Global Impression of Change (CGIC).

21. The use of claim 9, wherein functional status is measured by the patient’s Short-Form General Health survey (SF—36) Subject Reported Questionnaire score.

22. The use of claim 9, wherein quality of life is assessed by SF-36, EQSD, Subject Global Impression (SGI), or ian Global Impression of Change (CGIC).

23. The use of claims 21 or 22, wherein the patient’s SF—36 mental component summary score (MSC) is improved and/or wherein the patient’s SF-36 physical component summary sore (PSC) is improved.

24. The use of claim 9, wherein e is ed by the EQSD, the patient’s d Fatigue Impact Scale (MFIS) score or the French valid version of the Fatigue Impact Scale (EMlF-SEP) SCOI‘C .

25. The use of claim 9, wherein symptom severity on work is measured by the work productivity and activities impairment General Health (WPAI-GH) questionnaire.

26. The use of any one of claims 1-25, wherein the medicament is prepared for oral administration.

27. The use of any one of claims 1—26, wherein the medicament is prepared for administration daily, more often than once daily, or less often than once daily.

28. The use of any one of claims 3-27 wherein the ment comprises a unit dose of laquinimod of less than 0.6 mg.

29. The use of any one of claims 3—27, wherein the medicament comprises a unit dose of laquinimod of 0. 1 -40.0 mg.

30. The use of claim 29, wherein the medicament comprises a unit dose of laquinimod of 0.1-2.5 mg/day, O.25-2.0 mg or 0.5-1.2 mg.

31. The use of any one of claims 3-30, wherein the medicament comprises a unit dose of imod of0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg or 2.0 mg.

32. The use of any one of claims 1—31, wherein the medicament is prepared for administration via aneous ion or intramuscular injection.

33. The use of claim 32, wherein a) the interferon-B is interferon beta-la and the medicament is prepared for administration intramuscularly at 30 mcg, once weekly; b) the interferon-B is interferon b and the medicament is prepared for administration subcutaneously at 0.25 mg, every other day; or c) the interferon-B is interferon beta-1a and the medicament is ed for administration subcutaneously at 22—44 mcg, three times a week.

34. The use of any one of claims 1—33, where the ment further comprises or is prepared for use in combination with nonsteroidal anti-inflammatory drugs (NSAIDS), salicylates, slow- acting drugs, gold compounds, hydroxychloroquine, sulfasalazine, combinations of slow— acting drugs, corticosteroids, cytotoxic drugs, immunosuppressive drugs and/or antibodies.

35. The use of any one of claims 1-34, wherein the medicament is prepared for periodic administration for at least 3 days, more than 30 days, more than 42 days, 8 weeks or more, at least 12 weeks, at least 24 weeks, more than 24 weeks or 6 months or more.

36. The use of any one of claims 1-35, wherein the medicament inhibits a m of ing multiple sis by at least 20%, at least 30%, at least 50%, at least 70%, more than 100%, more than 300% or more than 1000% .

37. The use of any one of claims 1—36, wherein each of the amount of laquinimod when taken alone, and the amount of eron—B when taken alone is effective to treat the human patient, or wherein either the amount of laquinimod when taken alone, the amount of interferon-B when taken alone, or each such amount when taken alone is not effective to treat the human patient.

38. A package comprising: a) a first pharmaceutical composition comprising an amount of laquinimod and a pharmaceutically acceptable carrier; b) a second pharmaceutical composition comprising an amount of interferon—B and a pharmaceutically able carrier; and c) instructions for use of the first and second pharmaceutical compositions together to treat a human patient afflicted with le sclerosis or presenting a clinically isolated syndrome, wherein the amount of laquinimod and the amount of interferon-B when taken er are more effective to treat the human patient than each agent at the same amount is administered alone.

39. The package of claim 38, wherein the first pharmaceutical composition is in liquid form, in solid form, in capsule form or in tablet form.

40. The package of claim 39, wherein the tablets are coated with a coating which inhibits oxygen from contacting the core, and/or the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, and/or pigment.

41. The e of any one of claims 38-40, wherein the first pharmaceutical composition further comprises mannitol, an alkalinizing agent, an ion reducing agent, a lubricant, and/or a filler, wherein: a) if the first pharmaceutical composition further comprises an alkalinizing agent, it is preferably meglumine, b) if the first pharmaceutical composition r comprises a lubricant, i) it is preferably present in the composition as solid particles and/or ii) it is preferably sodium stearyl fumarate or magnesium stearate, c) if the first pharmaceutical composition further comprises a filler, i) it is preferably present in the composition as solid particles and/or ii) it is preferably lactose, lactose monohydrate, , isomalt, mannitol, sodium starch glycolate, sorbitol, lactose spray dried, e anhydrouse, or a combination thereof, preferably the filler is mannitol or lactose drate.

42. The e of any one of claims 38-41, n the first pharmaceutical composition is stable and free of an alkalinizing agent or an oxidation reducing agent, preferably the first pharmaceutical composition is free of an alkalinizing agent and free of an oxidation reducing agent.

43. The package of any one of claims 38-42, wherein the first pharmaceutical composition is stable and free of disintegrant.

44. The package of any one of claims 38-43, further comprising a desiccant, preferably the desiccant is silica gel.

45. The package of any one of claims 38-44, wherein the first ceutical composition is stable has a moisture content of no more than 4%.

46. The package of any one of claims 38-45, wherein laquinimod is present in the ition as solid particles.

47. The package of any one of claims 38-46, wherein the package is a sealed packaging having a moisture bility of not more than 15 mg/day per liter, preferably the sealed package is a blister pack in which the m moisture permeability is no more than 0.005 mg/day.

48. The package of claim 47, wherein the sealed package is a bottle, preferably the bottle is closed with a heat induction liner.

49. The package of claims 47 or 48, wherein the sealed package ses an HDPE bottle.

50. The package of any one of claims 47-49, wherein the sealed package comprises an oxygen absorbing agent, ably the oxygen absorbing agent is iron.

51. The package of any one of claims 38-50, wherein the amount of laquinimod in the first composition is less than 0.6 mg or 01-400 mg, preferably 0.1-2.5 mg, 0.25—20 mg or 0.5-1.2

52. The package of claim 51, wherein the amount of laquinimod in the first composition is 0.25 mg, 0.3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg or 2.0 mg.

53. Use according to claim 1, substantially as herein described with reference to any one of the Examples and/or