WO2016075543A1 - Treatment of multiple sclerosis with combination of laquinimod and a phosphodiesterase-4 (pde4) inhibitor - Google Patents

Abstract

This invention provides a method of treating a subject afflicted with multiple sclerosis {MS} or presenting a clinically isolated syndrome (CIS) comprising administering to the subject laquinimod as an add-on to or in combination with a phosphodiesterase Type 4. { PDE45 inhibitor. This invention also provides a package and a pharmaceutics X composition comprising laquinimod and a PDE4 inhibitor for treating a subject afflicted with MS or presenting CIS, This invention also provides laquinimod for use as an add-on therapy or in combination with a PDE4 inhibitor in treating a subject afflicted with MS or presenting CIS, This invention further provides use of laquinimod and a PDE4 inhibitor in the preparation of a combination for treating a subject afflicted with MS or presenting CIS.

Description

Trea ment 0£ Multiple gelerogis_^ With mbi a io Of La¾uiniaiod

This application claims priority of U.S. Provisional Application No. 62/079., 322, filed November 13, 2014, the entire content of which is hereby incorporated by reference herein.

Throughout this application, 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. The disclosures of these documents and publications referred to herein are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art to which this invention pertains .

Background Multiple Sclerosis (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, psychological, social and. financial impact oxi subjects and their families, friends and bodies responsible for health care (EMEA Guideline, 2006} .

A clinically isolated syndrome {CIS} is a single monosymptomatic attack suggestive of MS, such, as optic neuritis, brain stem symptoms, and partial mye tis . Patients with CIS that experience a second clinical attack are generally considered to have clinically definite multiple sclerosis iCDMS) , 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 subjects with RRMS have an initial relapsing-remitting course for 5-15 years, which then advances into the secondary progressive MS (SP S) disease course. There are currently a number of disease-modifying medications approved for use. in relapsing MS {RMS ) .. which inc.lx3.des RRMS and SPMS {The Disease Modifying Drug Brochure, 2006} . These include interferon beta 1-a {Avonex® a d Rebif®) , interferon beta I-b (Betaseron^®) , glatiramer acetate (Copaxone^®) , mitoxantrone (Novantrone®) .. natal zumab {Tysabri®} and Pixsgoliraod (Gilenya®) .

Immunosuppressants or cytotoxic agents are used in some subj ects after failure of conventional therapies. However, the relationship between changes of the immune response induced by these agents and the clinical eff cacy in MS is far from settled {EMEA Guideline, 2006; .

Other therapeutic approaches include symptomatic treatment which refers to ail therapies applied to improve the symptoms caused by the disease (EMEA Guideline, 2006} and treatment of acute relapses with corticosteroids. While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some subjects, Phosphodiesterase- {P E ) Inhibitors

Phosphodiesterases (PDEs) are enzymes involved in the regulation of intracellular levels of the second messengers cyclic adenosine monophosphate (c¾MP) and cyclic guanosine monophosphate (cGMP) . These enzymes hydrclyze the cyclic nucleotides to the corresponding nucleoside 5 ' -monophosphates - Nine PDE subtypes have been identified; these differ in their substrate specificity and mode of activation. The type 4 PDE (PDE4) hydroiyses cAKP, is activated by elevated levels of cAMP, and is inhibited by, e.g. , rolipram. Inhibition of enayme activity has been shown to modulate the activity of cells of the immune system. The production of tumor necrosis factor (TNF) a by activated monocytes and macrophages is inhibited., and cytokine secretion and proliferation of type 1 T helper cells are suppressed. Both immune cell activation and their concomitant induction of cytokine secretion are implicated in MS, (Dinter, 2000} , Examples of PDE 4 inhibitors include rolipram, ro lumilast, cilomilast, aprem last, and some flavonoids such as dioclein. (Kumar et ai, , 2003}

Rolipram Rolipram {±) -4- {3 ~cyciopentylox ~4methoxyphenyl} -2 -pyro.1idone increases the intracellular availability of cAMP by selective inhibition of PDB4. Its efficacy and safety as n antidepressant: in humans have been documented in. numerous studies. Rolipram has also shown efficacy in autoimmune encephalomyelitis (EAE) animal model of KS (Sonsmer et al. , 1995, Bielekov et al. , 200:55. However, a subsequent proof-of principle phase J./Il open label clinical trial was stopped prematurely because the drug was poorly tolerated and because of saf ty concerns ; the drug induced an increase, rather than, decrease in the brain inflammatory activity measured by contrast -enhancing lesions (CEL) on brain RI. (Bielekov et al. , 2009) .

Laquinimod (TV-5600) is a novel synthetic compound with high oral bioavailability which has been suggested as an oral formulation for the treatment of Multiple Sclerosis (MS) {Polmaxi, 2005;

Sandbex-g~Wol Iheim, 2005; Comi et al 2008) , Laquinimod and its sodium salt form are described, for example, in U.S. Patent No.

6,077,851, The mechanism of action of laquinimod is not fully unde stood .

Animal studies show it causes a Thl (T helper 1 ceil, produces pro-inflammatory cytokines) to Th2 (T helper 2 cell, produces anti-inf1ammatory cytokines} shift with an an i - nflammatory profile (Yang,. 2004; Br ck, 2011) . toother study demonstrated {mainly via the NFk3 pathway) that laquinimod induced suppression of genes related to antigen presentation, and corresponding inflammatory pathways {Gurevich, 2010) . Other suggested potenti l mechanisms oil action include inhibition of leukocyte migration into the CNS, increase of axonai integrity, modulation of cytokine produc ion, and increase in levels of brain-derived neurotrophic factor (BDNF) (Runeb &n, 2006; Bruck, 2011) .

Laquinimod showed a favorable safety and tolerability prof le in two phase III trials {Results of Phase III BRAVO Trial Reinforce Unique Profile of Laquinimod for Multiple Sclerosis Treatment; 'leva Pharma, Active Biotech Post Positive Laquinimod Phase 3 ALLEGRO Results ) .

TUPAC : 5 ~ch^'.Loro-i?-eth.yl-4 -hydrox -1 -methyl-2 --oxo-i?-phenyl~1 , 2 ·^■ d.ihydroguino1ine~ 3 ~carboxatnide

The administ ration of two drags 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., metabolism, 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 othe . For instance, one drug may inhibit, activate or induce the production of enzymes involved in a metabolic route of elimination of the other drug (Guidance for Industry, 2012} - In one example _f combined administration of fingolimod and interferon (IFN) has been experimentally shown to abrogate the clinical eff ctiveness of either therapy. (Bred 2000) In another experiment, it was reported that the addition of prednisone in combination therapy with ΙΡΝ-β antagonized its up-regu ator effeot. Thus, when two drugs ax's administered to treat the same condition, it is unpredictable whether each will complement, have no effect on, or interfere with, the therapeutic activity of the other in a human subject.

Not only may the interaction between two drugs affect the intended therapeutic activity of each drug, but the interaction may increase the levels of toxic metabolites 'Guidance for Industry, 1999) . The interaction may also heighten or lessen the side effects of each drag. Hence, upon administration cf two drugs to treat a disease, it is unpred c able what change will occur in the negative side profile of each drug. In one example, the combination of: natalizutnab and interferon β-la was observed to increase the risk of unanticipated side effects. (Vollmer, 2008; Rudick 2006; Kleinschmidt-DeKasters, 2005; Langer-Gould 005)

Additionally, it is difficult to accurately predict when the effects of the interaction between the two drugs will become manifest. For example, metabolic interactions between drags may become apparent upon the initial administration of the second drug, after the two have reached a steady-state concentration or upon discontinuation of one of the drugs (Guidance fox- Industry, 1399) . Therefore, the state of the art at the time of filing is that the effects of combination therapy of two drugs, in particular laquinimod and a PDE inhibitor, e.g., rolipram, cannot be predicted until the results of a combination study are available.

Figure 1 is a graphical representation of the experimental results from Example 1. The graph shows the clinical score or the ΕΆΕ rodents in each group (on the y-axis) against the days after induction of the disease (on the x-axis) .

Figure 2 is a graph of olipratR Mean lasma Concentration-time Profile in mice Sollowing a single PO dose of Laquinirood from Example 2 ,

Figure 3 is a graph of Laquinimod Mea Plassna Concentration-time

Profile in mice following a single PO dose of Rolipram from Example 2.

The subject invention provides a method of treating a sub ect afflicted with multiple sclerosis {MS} or presenting a clinically isolated syndrome (CIS) comprising administering to the subject an amount of laquinimod and an amount of a phosphodiesterase Type 4 (P E45 inhibitor.

The subject 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 a PDE4 inhibitor and a pharmaceutically acceptable carrier; and c) instructions fox- use of the first and second pharmaceutical compos tions together to treat a subject, afflicted with MS or presenting a CIS . The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject, afflicted with MS or presenting a CIS, which comprises $ a) one or mere unit doses, each such unit dose comprising; i} an amount of laquinimod and ii; an amount of a PDE4 inhibitor, wherein the respective amounts of said laquinimod and said PBE4 inhibitor in said unit doss are effective, upon concomitant administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container" further containing or comprising labeling direct ing the use of said package in the treatment of said subject.

The subject invention also provides a pharmaceut cal composition comprising an amount of laquinimod and an amount of a PDB4 inhibitor. The subject invention also provides a process of preparing a pharmaceutical composition comprising an amount of laquinimod and an amount of PDE4 inhibitor, comprising 1} obtaining an amount of laquinimod and an amount of PDE4 inhibitor, and 2) admixing the laquinimod and the PDE4 inhibitor with a pharmaceutically acceptable carrier to make the pharmaceutical composition.

The subject invention also provides a pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with MS or presenting a CIS., which comprises: a) an amount of laquinimod; b} an amount of a PDE4 inhibitor, wherein the respective amounts of said laquinimod and said PDE4 inhibitor in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said composition, to treat the subject.

The subject invention also provides a pharmaceutical composi ion comprising an amount of laquinimod for use in treating a subject afflicted with MS or presenting a CIS as an add-on therapy or in combination with a PDE4 inhibitor. The subject, invention also provides a pharmaceutical composition comprising an amount of laquinimod for use in treating a subjec afflicted, with MS or presenting a CIS simultaneously, contemporaneously or concomi antly with a PDE4 inhibitor.

The subject invention also provides a process of preparing a pharmaceutical composition prepared for treating a subject afflicted with MS or presenting a CIS using an amount oil laquinimod., either as an add-on therapy to or in corafo.inat.ion with an amount of PDE4 inhibitor, comprising 1) obtaining an amount of laquinimod, and 2) admixing the laquinimod with a pharmaceutically acceptable carrier.

The subject invention also provides a pharmaceutical composition comprising n amount of a PDE4 inhibitor for use treating a subject afflicted with MS or presenting a CIS a.s an add-on therapy or in combination with laquinimod. The subject invention also provides a pharmaceutical composition comprising an amount of a PDS4 inhibitor for use treating a subject afflicted with MS or presenting a CIS simultaneously, contemporaneously or concomitantly with laquinimod. The subject invention also provides laquinimod. for use as an. addon therapy or in combination with a PDE4 inhibitor in treating a subject a flicted with MS or presenting a CIS . The subject invention also provides a FDE4 inhibitor for use as an add-on therapy or in comb nation with laquinimod in treating a subject afflicted with MS or presenting a CIS.

The subject .invention also provides use of an amount of laquinimod and an amount of a PDS4 inhibitor in the preparation of a combination for treating a subject afflicted with MS or presenting a CIS wherein the laquinimod and the PDE4 inhibitor are prepared to be administered simultaneously., contemporaneously or concomitantly.

The subject invention aleo provides use of an amoun of laquinimod in the manufacture of a medicament for treating a subject afflicted with MS or presenting a CIS wherei the laquinimod is prepared as an add-on therapy to or in combination with an amount of a PDS4 inhibitor, and wherein the amount of laquinimod and the amount of PDE4 inhibitor when taken together are effective to treat the subject, The subject invention also provides use of an amount of laquinimod and an amount of PDE4 inhibitor in the manufacture of a medicament for treating a subject afflicted with MS or presenting a CIS, wherein the amount of laquinimod and an amount, of PDE4 inhibitor when taken together are effective to treat the subject.

The subject invention also provides a process of preparing a medicament prepared for treating a subject afflicted with MS or presenting a CIS using an amount of laquinimod, either as an addon therapy to or in combination with an amount of PDE4 inhibitor, comprising 1) obtaining a pharmaceutical composition comprising an amount of laquinimod and a pharmaceutically acceptable carrier, and 2) packaging the pharmaceutical composition to make the medicament. The subject invention also provides a process of preparing a medicament prepared for treating a subjec afflicted with MS or presenting a CIS using an amount of laquinimod and an amount of PDS4 inhibitor, comprising 1} obtaining a pharmaceutical composition comprising an amount of laquinimod, an amount of PDE4 inhibitor, and a pharmaceutically acceptable carrier,, and 2) packaging the pharmaceutical composition to make the medicament.

ailed ^Description of the Invention

The subject invention provides a method of treating a subject afflicted with multiple sclerosis (MS) or presenting a clinically isolated syndrome (CIS) comprising administering to the subject an amount of laquinimod and an amount of a phosphodiesterase Type 4 (PDE4) inhibitor. In one embodiment of the present invention, the method comprises periodically admin stering to the subject an amount of laquinimod and an amount o£ the P E4 inhibitor, wherein the amount of laquinimod and the amount of the PD34 inhibitor when taken together is more effective to treat the subject than when each agent at the same respective amount is administered alone.

In a embodiment, the MS is relapsing MS. Irs another embodiment, the relapsing MS is relapsing-remifc ing MS.

In one emodiment, the amount of laquinimod and the amount of the PDE inhibitor when taken together is effective to reduce a symptom of MS in the subject. In another embodiment, the symptom is a RI -monitored MS disease activity, relapse rate, accumulation of physical disability, i requency of relapses, decreased time to confirmed disease progression, decreased time to confirmed relapse, frequency of clinical exacerb on, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, deterioration of visual function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormali ies observed in whole Brain TR histogram, deterioration in general health status, functional status, quality of life, and/or symptom severity on work.

In one embodiment, the amount of laquinimod and the amount of the PDE4 inhibitor when taken together is effective to a) decrease or inhi bit reduction of brain volume, b) increase time to confirmed disease progression, c) decrease abnormalities observed in whole Brain MTR histogram, or d) reduce cognitive impairment.

In an embodiment , brain volume is measured by percent brain volume change (PBVC) . In another embodiment, time to confirmed diseass progression is increased by 20-60%. In another embodiment , cognitive impairment is assessed by the Symbol Digit Modalities Test (S ) score. In another embodiment, the accumulation of physical disability is measured by Kurtzke Expanded Disability Status Scale (EDSS) score, or is assessed by the time to confirmed disease progression as measured by EDSS scor .

In one embodiment, the subject had an E!DSS score of 0-5.5 at baseline, an EDSS score of 1, 5-4.5 at baseline or an EDSS score of 5.5 or greater at baseline. In another embodiment , confirmed disease progression is a 1 point or a 0.5 point increase of the EDSS score .

In one embodiment , impaired mobility is assessed by the Timed-25

Foot Walk test, the 12 -Item MS Walking Scale ( SWS-12) self -report questionnaire , the Ambulation Index (AI) , the Six-Minute Walk (SMW) Test or the Lower Extremity Manual Muscle Test (LBMMT) Test, In another embodiment, general health status is assessed by the EurcQoL (KQSD) questionnaire, Subject Global Impression (SGI) or Clinician Global Impression of: Change (C6IC) , In another embodiment , functional status is measured by the subject's Short- Form General Health survey (SF-36) Subject Reported Questionna e score. In another embodiment, quality of life is assessed by SF~ 36, EQ5D, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC) . In another embodiment, the subject's SF-36 mental componen summary score (MSG) is improved. In another embodiment , the subject's SF-36 physical component summary sore (PSC) is improved. In another embodiment, fatigue is assessed by the EQ5D, the subject's Modified Fatigue Impact Scale ( FXS) score or the French valid versions of the Fatigue Impact Scale (T5 I.F -SEP) score. In another embodiment, symptom severity on work is measured by the work produc ivity and activities impairmen General Health (WPAI-GH) questionnaire .

In an embodiment, laquinimod is laquinimod sodium. In another embodiment, the PDE4 inhibitor is rolipram, roflumilast, cilomilas , apremilast, or diociein. I one embodiment , the laquiniraod and/or the PDE4 inhibitor is administered via oral administration . In another embodiment, the laquinimod and/or the PDB4 inhibitor is administered daily. In another embodiment, the laquinimod and/or the PDE4 inhibitor is administered more often than once daily. In another embodiment , the laquinimod and/or the PDE4 inhibitor is administered less often than once daily.

In one embodiment , the amount of laquinimod administered is less than 0.6 mg/day. In another ecabodiment , the amount of laquinimod administered is 0.1-40.0 mg/day. In another embodiment , the amount of laquinimod administered is 0.1-2.5 mg/day. In another embodiment , the amount of laquinimod administered is 0.25-2.0 mg/day. In another embodiment, the amount of laquinimod administered is 0.5-1.2 mg/day. In another embodiment, the amount of laquinimod administered is 0.25 mg/day, 0.3 mg/day, 0.5 mg/day, 0,6 mg/day_f 1.0 mg/day, 1,2 mg/day, 1.5 mg/day, 1,8 mg/day or 2.0 mg/day.

In one embodimen , the amount of the ΡΌΕ4 inhibitor administered is 0.1-100 mg/day. In another embodiment, the amount of the PDE4 inhibitor administered is 0.5-60 mg/day. In another embodiment, the amount of the PDE4 inhibitor administered is about 0.5, 1.0, 5.0, 10.0, 15.0, 20.0, 25.0 30.0, 4.0.0., 50.0, or SO.O mg/day. In another embodiment, the amount of the PDS4 inhibitor administered is 0.5, 1.0, 5,0, .10.0, 15.0, 20.0, 25.0, 30.0, 40,0, 50,0, or SO.O mg/day,

In one embodiment , a loading dose of an amount different from the intended dose is administered for a period of time at the start of the periodic administration of at least one of laquinimod and the PDE4 inhibitor. In another embodiment, the subject is receiving laq inimod therapy prior to initiating the PDE4 inhibitor therapy. In another embodiment , the subject is receiving the PDE4 inhibitor therapy prior to initiating laquinimod therapy. In another embodiment, the subject is receiving a first therapy for at least 8 weeks, at least 10 weeks, at least 24 weeks, at .least 28 weeks,, at least 48 weeks or at least 52 weeks prior to initiating a second therapy. In yet another embodiment , the method further comprises administration of nonsteroidal anti -inflammatory drugs {NSAIDs} , salicylates, slow-acting drugs, gold compounds, hydroxychloroguine, sulfasalazine, corticosteroids, cytotoxic drugs, immunosuppressive drugs and/or antibodies.

In one embodiment , the periodic administration of laquinimod and the PDE4 inhibitor continues for at least 3 days, for more than 30 days, for more than 42 days, for 8 weeks or more, for at least 12 wee!cs, for at least 24 weeks or for S months or more. In another embodiment, the administration of laquinimod and the PDE4 inhibitor inhibits a symptom of relapsing MS by at least 20%, by at least 30%, by at least 50%, by at least 70%, by more than 100%, by more than 300% ox- by more than 1000%'.

In one embodiment , each of the amount of laquinimod when taken alone, and the amount of the ΡΌΕ4 inhibitor when taken, alone is effective to treat the subject. In another embodiment, either the amount of laquinimod when taken alone, the amount of the PDE4 inhibitor when taken alone, or each such amount when taken alone is not effective to treat the subject. In yet another embodiment, the subject is a human patient.

The subject 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 a PDE4 inhibitor and a pharmaceutically acceptable carrier; and c) instructions for use of the first and second pharmaceutical compositions together to treat a subject afflicted with MS or presenting a CIS .

In one embodiment, the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical compositions are in an aerosol, an inhalable powder, an injectable, a liquid, a solid, a capsule or a tablet form. In another embodiment, the first pharmaceutical composition, the second pharmaceutical composition, or both the first and the second pharmaceutical compositions are in a liquid or a solid form. In yet another embodiment, the first pharmaceutical composition,. the second pharmaceutical composition, or both the first and the second pharmaceutical compositions are in capsule form or in tablet form.

In one embodimen , 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, or pigment.

In an embodiment,, the first, pharmaceutical composition further comprises mannitol , an alkalinizing agent, an oxidation reducing agent, a lubricant , and/or a filler. In another embodiment , the alkalinizing agent is meglumin . In another embodimen , the lubricant is present in the composition as solid particles . In another embodiment , the lubricant is sodium stearyl fumarate or magnesium stearate. In another embodiment, the filler is present in the composition as solid particles. In another embodiment, the filler is lactose, lactose monohydrate, starch, isomalt, mannitol, sodium starch glycol te, sorbi ol, lactose spray dried, lactose anhydrouse, or a combination thereof. In another embodiment, the filler is mannitol or lactose monohydrate .

In one embodiment , the irst pharmaceutical composition is stable and free of an alkalinizing agent or an oxidation reducing agen . In another embodimen , the irst pharmaceutical composition is ree of an alkalinizing agent and f ee of an oxidation reducing agent . In yet another embodiment, the first pharmaceutical composition is stable and free of disintegrant .

In one embodiment, the package further comprises a desiccan . In another embodiment, the desiccant is silica gel .

In an embodiment , the first pharmaceutical compositio is stable and has a moisture content of no more than 4%. In another embodiment, laquinimod is present in the composition as solid particles. In another embodiment, the package is a sealed packaging having a moisture permeability of not more than 15 mg/^'day per liter. In another embodiment, the sealed package is a blister pack in which the maximum moisture permeability is no more than 0,005 tng.day. In another embodiment, the sealed package is a bottle and/or comprises an HDPE bottle. In another embodiment, the bottle is closed with a heat induction liner.

In one embodiment , the sealed package comprises an oxygen absorbing agent. In another embodiment., the oxygen absorbing agent is; i on.

In one embodiment, the amount of laquinimod in the first composition is less tha 0.6 rag. In another embodiment , the amount of laquinimod in the first composition is 0.1-40.0 mg. In another embodiment, the amount of laquinimod is 0.1-2,5 mg. In another embodiment, the, amount of laquini od is 0.25-2.0 mg. In another embodiment, the amount of laquinimod is 0.5-1.2 mg, In another embodiment, the amount of laquinimod 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 .

In one embodiment, the amount of the PDE4 inhibitor is 0.1-100 mg. In another embodiment, the amount of the PDS4 inhibitor is 0.5-60 rag. In another embodiment, the amount of the PDE4 inhibitor is about 0.5, 1.0, 5.0, 10,0, 15.0, 20.0, 25.0, 30,0, 40,0, 50.0, or 60.0 mg. In another embodiment, the amount of the PDE4 inhibitor i& 0.5, 1,0, 5.0, 10.0, 15.0, 20.0, 25.0, 30,0, 40.0, 50,0, or S0.0 mg .

In an embodiment , the amount of laquinimod and the amount of the PDE4 inhibitor are prepared to be administered simultaneously, contemporaneously or concom tantly.

The subject invention also provides a therapeutic package for dispensing to, or for use in dispensing to, a subject afflicted with MS or presenting a CIS , which comprises; a) one or more unit doses, each such unit dose comprising; i ) an amount of laquinimod and ii) an amount of a PBE4 inhibitor, wherein the respective amounts of said laquinimod and said PDE inhibitor in said unit dose are effective, upon concomitant administration to said subject, to treat the subject, and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment:, of said subject.

1x3. one embodiment, the respective amounts of said laquinimod and said PDE4 inhibitor in said unit dose when taken together is more effective to treat the subject than when compared to the administration of said laquinimod in the absence of the PDS4 inhibitor or the administration of the PDS4 inhibitor in the absence of said laquinimod. In another embodiment , the PDS4 inhibitor is rolipram, roflumilast, cilomilast, apremilast, or diocl in.

The subject invention also provides a pharmaceutical composition comprising an amount of laquinimod and an amoun of a PDE4 inhibitor. In one embodiment, the pharmaceutical composition consists essentially of an amount of laquinimod and an amount of a PDE4 inhibitor. In another embodiment, the pharmaceutical composition is for use in treating a subject afflicted with MS or presenting a CIS, xtfherein the laquinimod and the PDE4 inhibitor are prepared to be administered simultaneously, contemporaneously or concomitantly .

I an embodiment, laquinimod is laquinimod sodium. In another embodiment, the PDE inhibitor is; rolipram, roflumilast, cilomilast, apre ilast, or dioclein. In one embodiment the pharmaceutical composition is in an aerosol, an inhalabl.es powder, an injectable, a liquid, a solid, a capsule or a 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 celluiosie polymer, a det ckifier, a gloss enhancer, or gment .

In. an embodiment: the pharmaceutical composition further comprises mannitol, an alkaiinizing agent, an oxidation reducing agent, a lubricant or a f. ller. In another embodiment , the alkaiinizing agent is meglumine . In another embodiment , the lubricant is present in the composition as solid particles. In another embodiment, the lubricant is sodium stear l furaarate or magnesium stearate. In another embodiment , the friiler is present in the composition as solid particles. In another embodiment, the filler is; lactose, lactose monohydrate , starch, isomalt, manni ol , sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse , or a combination thereof. In another embodiment, the filler is mannitol or lactose monohydrate. In one embodiment , the pharmaceutical composition is free of an alkalinizing agent or an oxidation reducing agent;. In another embodiment., it is free of an alkalinizing agent and free of an oxidation reducing agent . In yet another embodiment, it is stable and free of disintagrant . In one 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 0.1-40.0 mg. In another embodiment, the amount of laquinimod is 0,1-2.5 mg. In another embodiment, the amount of laquinimod is 0.25-2,0 mg. In another embodiment , the amount of laquinimod is 0.5-1.2 mg. In another embodiment, the amount of laquinimod is G.2S mg, 0,3 mg, 0.5 mg, 0.6 mg, 1.0 mg, 1.2 mg, 1.5 mg, 2.0 mg.

In an embodiment, the amount of the PDE4 inhibitor is 0.1-100 mg.

In another embodiment, the amount of the PDE-4 inhibitor is 0,5 -SO mg. In another embodiment, the amount of the PDE4 inhibitor is about 0.5, 1.0, 5,0, 10,0, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, ox- SCO mg. In yet another emboditnent , the amount of the PDE4 inhibitor is 0,5, 1.0, 5.0, 10.0, 15. Q, 20,0, 25.0, 30.0, 40.0, 50.0, or 60,0 mg. The subject invention also provides a process; of preparing a pharmaceutical composition comprising an amount of laquinimod and an amount of PDE4 inhibitor, comprising 1) obtaining an amount of laquinimod and an amount of PDE4 inhibitor, and 2) admixing the laquinimod and the PDE4 inhibitor with a pharmaceutically acceptable carrier to make the pharmaceutical composition. The subject invention also provides a pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with MS or presenting a CIS, which comprises; a; an amount of Iaquinimod; b) an amount of a PDE inhibitor, wherein the respective amounts of. said iaquinimod and said PDE4 inhibitor in said composition are effective, upon concomitant administra on to said subject of one or »re of said unit dosage forms of said composition, to treat the subject. In one embodimen , the respective amounts of said Iaquinimod and the PDE inhibitor in said unit dose when taken together is Tftore effective to treat the subject than when compared to the administration of said Iaquinimod in the absence of: the ΡΠΕ inhibitor or the administration of the PDE4 inhibitor in the absence of said Iaquinimod, The subject invention also provides a pharmaceutical composition comprising an amount of Iaquinimod for use in treating a subject afflicted with MS or presenting a CIS as a add-on therapy or in combination with a PDE4 inhibitor,

'The sub ect invention also provides a process; of preparing a pharmaceu cal compositio prepared for treating a subject afflicted with MS or presenting a CIS using an amount, of Iaquinimod, either as an add-on therapy to or in combination with an amount of PDE4 inhibitor, comprising 1} obtaining an amount of Iaquinimod, and 2) admixing the Iaquinimod with a pharmaceutically acceptable carrier.

The subject invention also provides a pharmaceutical composition comprising an amount of Iaquinimod for use in treating a subject afflicted with MS or presenting a CIS simultaneously, contemporaneously or concomitantly with a PDE4 inhibitor. The sub ect invention also provides a pharmaceutical composition comprising an amount of a ΡΌΕ4 inhibitor for use treating a subject afflicted with MS or presenting a CIS as an add-on therapy or in combination with Iaquinimod. The subject invention also provides a pharmaceutical composition compr sing an amount of a PDE4 inhibitor for use treating a subject afflicted with MS or pressenting a CIS simultaneously, contemporaneousl or concomitantly with Iaquinimod, The subjec invention also provides iaquinimod for use as an addon therapy or in combination with a PDE4 inhibitor in treating a subj set afflicted with MS or presenting a CIS.

The subject invention also provides a PDE4 inhibitor for use as an add-on therapy or in combination with Iaquinimod in treating a subject afflicted with MS or presenting a CIS,

The subject invention also provides use of an amount of Iaquinimod and an amount of a PDE4 inhibitor in the preparation of a combination for treating a subject afflicted with MS or presenting a CIS wherein the Iaquinimod and the PDK4 inhibitor are prepared to be administered simultaneously, contemporaneously or concomitantly.

In an embodiment of any of the pharmaceutical composition or use described above, the PDH4 inhibitor is rolipram, roflumilast, cilomilast, apremilast, or dioclein. The subject invention also provides use of an amount of Iaquinimod in the manuf cture of a medicament for treating a subject afflicted with MS or presenting a CIS wherein the Iaquinimod is prepared as an add-on therapy to or i combination w h an. amount of a PDE4 inhibitor, and wherein the amount of Iaquinimod and the amount of PDE4 inhibitor when taken together are effective to treat the subject.

The subject invention also provides use of an amount of Iaquinimod and an amount of PDE4 inhibitor in the manufacture, of a medicament for treating a subject afflicted with MS or presenting a CIS _f wherein the amount, of iaquinimod and an amount of: PDE4 inhibitor when taken together are effective to treat the subj ect . The subject invention also provides a process of preparing a medicament prepared for treating a subject afflicted with MS or presenting a CIS using an amount: of laquinimod, ei her as an addon therapy to or in combination with an amount of PDE4 inhibitor, comprising 1} obtaining a pharmaceutical composition comprising an amount of laquinimod and a pharmaceutical ly acceptable carrie j and 2) packaging the pharmaceutical composition to make the medicamen .

The subject invention also provides a process of preparing a medicament prepared for treating a subject afflicted with MS or presenting a CIS using an amount of laqu nimod and an amount of PDS4 inhibitor, comprising I) obtaining a pharmaceutical composition comprising an amount of laquinimod, an amount of PDE4 inhibitor, and a pharmaceutically acceptable carrier, and 2} packaging the pharmaceutical composition to make the medicament.

The PDE4 inhib tors; s described herein can be administered by way of oral, sublingual, injection including subcutaneous , intramuscular and intravenous, topical, int atracheal, intranasal, transdermal or rectal administration. The PDE4 inhibitors may be administered in admixture with conventional pharmaceutical carriers. The appropriate unit forms of administration include forms for oral administ ation, such as tablets, gelatin capsules, powders, grannies and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for injection including subcutaneous, intramuscular or intravenous admi atra oxi and forms for rectal administration. In one particular embodiment , oral administration is preferred.

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, 384,208, U.S. Patent No. 7,989,473, U.S. Patent Mo, 8,178,127. U.S. Application Publication No. 2010- ^■0055072.., U.S. Application. Publication No. 2012-00102.38, and U.S. Applica ion Publication No. 2012-0010239, each of which is hereby incorporated by reference in its entireties into this ap lication.

Use of laquinimod for treatment of various conditions, and the corresponding dosages and regimens, are described in U.S. Patent No, 6,077, 851 (multiple sclerosis, insulin-dependent diabetes raellitus, systemic lupus erythematosus , rheumatoid arthritis, i flamma ory bowel disease, psoriasis,, inflammatory resp atory disorder, atherosclerosis, stroke, and Alzheimer' 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 (3UNF) -related diseases), 15. S, Application Publication No. 2011-0218179 (active lupus nephritis), U.S. Application Publication No. 2011-0218203 (rheumatoid arthritis), U.S. Application Publication No, 2.011- 02172.95 (active lupus arthritis) _t and U.S. Application Publication No. 2012-0142730 (reducing fatigue, improving quality or life, and providing neuroprotection in MS patients) , each of which is hereby incorporated by reference in its entireties into this application.

A pharmaceutically acceptable salt of laquinimod as used in this application includes lithium, sodium, potassium, magnesium, calcium, manganese, copper, zinc, aluminum and iron. Salt formulations of laquinimod and the process f!or preparing the. same are described, e.g., in U.S, Patent No. 7,589,208 and PCT International Application Publication Ho. WO 2005/074899, 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 acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit can be in a fo m suitable for oral administration . Laquinimod can be administered alone but is generally mixed with a pharmaceutically acceptable carrier, and Co- dministered 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. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk, powders.

Tablets may contain suitable binders, lubricants, disintegrating agents , coloring agents, flavoring agents, flow-inducing agents, and melting agents. For instance, for oral administration in the unit dosage 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, starch, 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 bet - lactose, corn starch, natural and synthetic gums such s acacia, tx'agacant.h, or sodium alginate , povidone, carhoxy ethyicellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms includ sodium oleate, sodium stsarate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like. Disintegrators ixi.clude, without limitation, starch, methyl cellulose, agar, bantonite, xanthan gum, croscarmellose sodium, sodium starch giycoiate and the like. Specific examples of the techniques, pharmaceutically acceptable carriers and excipients that may foe used to formulate oral dosage forms of the present invention are described, e.g., in U.S. Patent No. 7,583,208, £»C International Application Publication Kos. WO 2005/074899, WO 2007/047863, and WO 2007/146248. General techniques and compositions for making dosage .orms useful in the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1973) Pharmaceutical Dosage Forms-, Tablets? (Liefoerman et ai , , 1981}; Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed, (Mack Publishing Company, Hasten, Pa, , 1985) ? Advances in Pharmaceutics! Sciences (David Ganderton, Trevor Jones, Eds.,, 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McG.in.ity, Sde. , 19.95); Aqueous Polymeric Coatings for Pharraaceufc cai Dosage Forms (Drugs and the Pharmaeeutical Sciences , Series 36 {James McGinity, Ed. , 1989} Pharmaeeut ical Particulate Carriers : Therapeutic Applications; Drugs and the Pharmaceutical Sciences, Vol 61 {Alain Holland, Ed. ₍ 1993); Drug Del very to the Gastrointestinal Tract (Ellis Korwood Books in the Biological Sciences. Series in Pharmaceutical Technology? J. G. Hardy, S. S. Davis, "live G. Wilson, Eds) . ; Modem Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol. 40 {Gilbert S. Banker, Christopher T. Rhodes, Eds) . These references in their entireties are hereby incorporated by reference into this applica ion.

Disclosed is a method for treating a subj ect , e.g. , human patient , afflicted with multiple sclerosis, e.g. , relapsing multiple sclerosis or presenting a CIS using laquinimod with a pDE4 inhibitor such as rolipram which provides a wore eff cacious treatment than each agent alone. The use of laquinimod for multiple sclerosis had been previously suggested in, e.g. , U.S. Patent No. 6,077,851. However, the inventors have surprisingly found, that the combination of laquinimod and PDE inhibitors such as rolipram is particularly effective for the treatment: of a subject afflicted with MS or presenting a CIS as compared to each agent alone .

For the foregoing embodiments , each embodiment d sclosed herein, is contemplated as being applicable to each of the other disclosed embodiments . For instance, the elements recited in the method embodiments can be used in the pharmaceu ical composition, package, and use embodiment described herein and vice versa.

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 laqudnimcd acid or a pharmaceutically acceptable salt thereof.

As used herein, a "phosphodiesterase 4 inhibitor" or "PDE inhibitor'-^* in an agent, which inhibits, attenuates, decreases, reduces, or antagonizes the activity of the Type 4 PDF, { DE } enzyme . Examples of PDE 4 inhibitors include rolipram, roflumilast, cilorailast, apresni las , and some flavonoids such as dioclein.

As used herein, an "amount" or "dose" of laquinimod or PDE4 inh bi cor as measured in milligrams refers to the milligrams of laquinimod acid or PDE4 inhibi or- present in a preparation, 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 preparation. Thus;, when in the form of a salt, e.g. 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.S4 mg} due to the presence of the additional salt ion.

As used herein, a "unit dose", "unit doses" and "unit dosage form is}" mean a single drug administration entity/^'entities .

As used herein, "about" i the. context of a numerical value or range means ±10% 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 formulation 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 ail, is a minority component of the composition by weight. Preferably, when a composition is "frse" of a component, the composi ion comprises less than 0.1 wfc%, 0,05 wt. . 0,02 wt%, or 0.01 t% 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 exeipient which neutralises protons in, and raises the pH of, the pharmaceutical composition in which it is used.

As used herein, "oxidation reducing agent" refers to a group of chemicals which includes an "a tioxidant"., a "reduction agent" and a "chelating agent",

As used herein, "antioxidant" refers to a compound or molecule that. inhibits the oxidation of other molecules. Examples of antioxidants include tocopherol , methionine, glutathione, tocotrienol , dimethyl glycine, betaine, butylated hydroxyaniaole, butylated hydroxytoluene , turraerin, vitamin E, ascorbyl paltnitate, tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben, butylated hydroxyaniaole, butylated hydroxytoluene, propyl gallate, sodium or potassium met&bieulfite, sodium or potassium sulfite, alpha tocopherol or derivatives thereof, sodium ascorbate, disodium edentate, BHA (butylated hydroxyanisole) , a pharmaceutically acceptable salt or ester of the mentioned compounds , and mixtures thereof.

The terns "antioxidant" as used herein is also exemplified by S!iavonoids such as those selected from the group of guercetin, orin, naringenin and hes eretin, taxifolin, afzelin, quercicrin, myricitrin, genistein, apigenin and biochanin h, lavone, fiavopiridol , soflavonoids such as the soy isoflavonoid, genistein, catechins such as the tea catechin epigailocatechin gallate, flavonol , epieatechin, hesperetin, chr sin, diosmin, hesperidin, iuteolin, and rutin.

As used herein, "reduction agent" refers to a compound exemplified by the group consisting of thiol -containing compound, thioglyceroi , mereaptoethanol, thiogiycol, bhiodiglycol, cysteine, thioglucose, dithiothreitol (DTT) , dithio~bis--reialeimidoethane (DT E) , 2,S--di~ tert-butyl -4-tnethylphenol (BHT) , sodium dithionite, sodium bisulphite, formamidine sodium metabisulphite, and ammonium bisulphite." As used herein, "chelating agent" refers to a compound exemplified by the group consisting of penicillamine , trientine, Ν,Ν' - diethyldi hiocarbamate {DDC) , 2,3,2' -tetraamine {2,3,2· -fcst) , neocuproins, Kf, IS, Ν' ,Ν' -tetrakis {2 -pyridylrasthyl ) ethylenediarnine

(TPS ) , I , lO-phenanthrolins ( PHE) , fcetraethylenepentamine , triethylenetetraansine and tris (2 -carboxyethyi ) phosp ine {TCEP} , ferricxaraine, CPS4, EDTA, deferoxamine B (DFO) as the methanesulfonate salt (also known as dssferrioxanilne B mesylate

(DFOM) 5 , desferal from Novartis (previously Ciba-Giegy) , and apof ri-.it.in.

As used herein,, a pharmaceu cal composition is "stable" when the composition preserves the physical stability/integrity and/or 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/7S%RH after 6 months or 3% at 55^»C,/7S% RH after two weeks, compared to their level in time zero.

As used herein, "combination" means an assemblage of reagents for use in therapy either by simultaneous 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 ΡΌΕ4 inhibitor. In this case, the combination may be the admixture or separate containers of the laquinimod and the PDS4 inhibitor that are combined just prior to administration. Contemporaneous administration refers to the separate admiriist ration of the laquinimod and the PDE4 inhibitor at the same time, or at. times sufficiently close together that, a additive or preferably syne gistic activity relative to the activity of either the laqui imod or the P E4 inhibitor alone is observed.

As used herein, "concomitant administration" or administering "concomitantly" means the administration of two agents given in close enough temporal proximately to allow the individual therapeutic effects of each agent to overlap. 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 regimen 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 laquini od therapy to a patient already receiving rolipram therapy.

As used herein, "effective" when referring to an amount of laquinimod and/or rolipram refers to the quantity of laquinirnod and/or rolipram that is sufficient to yield a desired therapeutic response. Efficacy can be measured by an improvement of a symptom of multiple sclerosis. Such symptoms can include a MRI-monitored multiple sclerosis disease activity, relapse rate, accumulation of physical disability, frequency of relapses, time to confirmed disease progression, time to conf rmed relapse, frequency of clinical exacerbation, brain atrophy, neuronal dysfunction, neuronal injury, neuronal degeneration, neuronal apoptosis, risk for confirmed progression, visual function, fatigue, impaired mobility, cognitive impairment, brain volume, abnormalities observed in whole Brain MTR histogram, general health status, functional status, quality of life, and/or symptom severity on work .

In an embodiment, an effective amoun is an amount that is sufficient to decrease or inhibit reduction of brain volume (optionally brain volume is measured by percent brain volume change (PBVCl), increase time to confirmed disease progression (e.g., by 20-60% or at least 50%), decrease abnormalities observed in whole Brain MTS histogram, decrease the accumulation of physical disability (optionally measured by urtzke Expanded Disability Status:- Scale (EDSS) score, e.g., wherein the accumulation of physical disability is assessed by the time to confirmed disease progression as measured by Kurtzke Expanded Disability Status Scale (HDSS) score) , improve impaired mobility {optionally assessed by the Timed-25 Foo Walk test, the 12 -Item Multiple Sclerosis Walking Scale (MSWS-12) self-report questionnaire, the. Ambulation Index (AI5 , the Six-Minute Walk (SM ) Test, or the Lower Extremity Manual Muscle Test (LEM T) Test) ., reduce cognitive impairment (optionally assessed by the Symbol Digit. Modalities Test (SDMT) score} , improve general health (optionally assessed by the EuroQoL (EQ5D) questionnaire, Subject Global Impression (SGI) or Clinician Global Impression oii Change (CGIC) ) , improve functional status {optionally measured by the subject's Short-Form General Health survey (SP-36) Subject Reported Questionnaire score) , improve quality of life (optimally assessed by SP-36 , EQ5D, Subjec Global Impression (SCI) or Clinician Global Impression of Change (CGIC) } , improve the subject's SF-36 mental component summary score (MSG.} and/or SF-36 physical component summary sore (PSC) , reduce level of fatigue (optionally assessed by the HQBD, the sub ect's Modified Fatigue Impact Scale (MF S; score or the French valid versions of the Fa igue impact Scale CEMIF-SEP} score) , or improve symptom severity on work (optionally measured by the work productivity and activities impairment General Health (WPAI--GH) questionnaire} . "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. The administration can be periodic administration. As used herein, "periodic administration" means repeated/recurrent administration separated by a period of time. The period of time between administrations is preferably consistent from time to time. Periodic administration can include administration, e.g., once daily, twice daily, three times daily, four times daily, weekly, twice weekly, three times weekly, four times a week and so on, etc.

"Treating" as used herein encompasses, e.g., inducing inhibition, regression, or stasis of a disease or disorder, e.g., Relapsing MS {R.MS} ,. or alleviating, lessening, 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 wi h multiple sclerosis and who has a high risk of developing CDMS.

"Inhibition" of disease progression or disease complication in a subject means preventing or reducing the disease progression and/or disease complication in the subject., A "symptom" associated with MS or RMS includes any clinical or laboratory manifestation associated with MS or RMS and is not limited to what the subject can feel or observe .

As used, herein, ^¾a subject afflicted with multiple sclerosis" or ^Ma subject afflicted with relapsing multiple sclerosis" means a subject who has been cli ically diagnosed to have multiple sclerosis or relapsing multiple sclerosis; {RMS) ,. which includes relapsing --remitting multiple sclerosis (SRMS5 and Secondary Progressive multiple sclerosis (SPMS) .

As used herein_! a subject at "baseline" is as subject prior to adminisstrat ion of iaquinimod and the PDE4 inhibitor as described herein.

A "patient at. risk of developing MS" {i.e. clinically definite MS) as used herein is a patient presenting any of the k own 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, environmental factors (geographical location, climate, diet, toxins, sunlight) , genetics (variation of genes encoding HLA-D Bl, IL7R"alpha and IL2R-alpha) , and immunological components (viral infection such as by Epstein-Barr virus, high avidity CD4* T cells, CDS'- T cells, anti-NP-L, anti-CSF 1.1.4, (Glc) ; . ^Clinically isolated syndrome {CIS}" as used herein refers to 1) a single clinical .attack (used interchangeably herein with "first clinical event" and "first: detsiye1 inating event") suggestive of MS, which, for example, presents as an episode of optic neuritis, blurring of vision, diplopia, involuntary rapid eye movement , blindness, loss of balance, tremors, ataxia, vertigo, clumsiness or a limb, lack of co-ordination, weakness o one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesi , burning sensations, muscle pains, facial pair,, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of speech, slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, f equency, incomplete emptying and incontinence) , bowel problems (including constipation and loss of bowel control) , impotence, diminished sexual arousal, loss of sensation, sensitivity 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 of MS measuring S mm or more in diameter .

"Relapse Rate" is the number of confirmed relapses per unit time. "Annualized 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 Disability Status Scale" or "EDSS" is a rating system that is frequen ly used for classifying and standardising 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 control 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, Visual, Mental, and Other (includes any other neurological findings due to MS) ( urtzke JF, 1983) . A "confirmed progression" of EDSS , or ^wconfirmed disease progression" as measured by EDSS score is defined as a i point increase from baseline EDSS if baseline EDSS was between 0 and 5.0, or a 0.5 point increase if baseline EDSS was 5,5- In order to be considered a confirmed progression, the change (either 1 point or 0.5 points) must be sustained for at least 3 months . In addition, confirmation of progres ion cannot be made during a relapse.

"Adverse event" or "AE" means any untoward medical occurrence in a clinical trial subject administered a medicinal product and which does not have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign including a abnormal laboratory finding, symptom, or diseases fcetnporally associated with the use of an investigational medicinal product, whether or not considered related to the investigational medicinal product . ^wGd-enhancing lesion" refers to lesions that result from a breakdown of the blood-brain barrier, which appear in contrast studies using gandolinium contrast agents. Gandolinium enhancement provides information as to the age of a lesion, as Gd-enhancing lesions typically occur within a six week period of lesion formation,

"Magne isatio Transfer Imaging" or "M I " is based on the magnetisation interaction (through dipolar and/or chemical exchange) between bxilk 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 decrease in signal (the net magnetization of visible protons is reduced) , depending on the magnitude of MT between tissue macromolecul.es and bulk water, "MT" or "Magnetiza ion Transfer"^' refers to the transfer of longitudinal magnetization from the hydrogen nuclei of water that have restricted motion to the hydrogen xmcl&i of water that moves with many degrees of freedom, With MTI, the presence or absence of macrotnolecules (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 magnetic resonance imaging (MR!) - 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, 200?) 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 function end the abil ty to move with or without assistance. Mobility can be evaluated by one or more of several tests including but not limited to Ambul tion Index, Time 25 foot walk, Six-Minute Walk (6M ) , Lower Extremity Manual Muscle Test (LEMMT) and EDSS. Mobility can also ha reported by the subject, for example by questionnaires, including but not limited to 12 -Item Multiple Sclerosis Walking Scale (MSWS-12) . Impaired Mobility refers to any impairment, difficulty or disability relating to mobil ty. ^wTi -weighted MR! image" refers to an M -image that, emphasizes Tl contrast by which lesions may be visualized. Abnormal areas in a Tl -weighted MR! image are "hypointense" and appear as dark spots. These spots are generally older lesions.

^1ST2 -weighted MRI image" refers to an M --image that emphasizes T2 contrast by which lesions may be visualized. T2 lesions represent new inflammatory activity.

The "'Six-Minute Walk (SMW) Test" is a commonly used test developed to assess exercise capacity in patients with COPD (Guyatt, 1.985) . It has been used also to measure mobility in multiple sclerosis patients (Clinical Trials Website) . The "Timed-25 Foot Walk"^' or "T25--F " is a quantitative mobility and leg function performance test baaed 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 instruction to start and ends when the patient has reached the 25 -foot mark. he 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 T2S--FW is the average of the two completed trials. This score can be used individually or used as part of the M^'SFC 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 Fatigue Impact Scale (EMIF-SBP) score, and European Quality of Life (EuroQoL) Questionnaire (EQ5D) , Other tests, including but not limited to Clinician Global Impression of Change (CGIC) and Subject Global Impression {SGI} , as wall as HQ- 3D, can be used to evaluate the general health status and quality of life of MS patients ,

"Ambulation Index" or "AI" is & 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 om 0 (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 assistance {e.g. , cane, walker, crutches) needed. (Hauser, 1983)

"EQ-5D" is a standardised questionnaire instrument fox- use as a measure of health outcome applicable to a range of health conditions and treatments. It provides a simple descriptive profile and a single index value for health status that can be used in the clinical and economic evaluation of health care as well as population health surveys. EQ--5D was developed by the "EuroQoL" Group which comprises a network of international, multilingual, multidisciplinary researchers, originally from seven centers in England, Finland, the Netherlands,. Norway and Sweden. The EQ-5D questionnaire is in the public domain and can be obtained from EuroQoL. "SF- 36 " is a multi-purpose, short: -form health survey with 36 questions which yields an 8-scale pro ile of functional health and well-being scores as well as psychometricaX ly~based physical and mental health summary measures 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 Qual tyMetr c , Inc. of Providence , EI .

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 benefit/risk ratio. It can be a pharmaceutically acceptable solvent, 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 provided by the invention. For example, "0.1-2. Smg/day" includes 0.1 mg/day, 0.2 mg/day, 0,3 mg/day, etc. up to 2.5 tng/day.

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

EXAMPLE 1¾ Assessment of 8£ f icac of La uiaimod In Combination With Rolipram In MOG-induced ERE

The objective of this study was to test the suppressive activity of laquinimod in combination wi h Rolipram i the MOG induced chronic Experimental Autoimmune Encephalomyelitis (EAE) model in C5731/6 mice. The C57B1/5 strain of mouse is an established chronic EAE model to test for the efficacy of candidate molecules tor the treatment of MS. Materials

* Rolipram, Apollo Scientific Ltd;

* Vehicle for Aeorvastatin (0.5 % Metfcocel) ;

Laquinii!iod

Pertnsis toxin, "Sigma", Code # 2SS0 · Myelin Oligodendrocyte Lipoprotein Novatide (MOG-35-S5) .;

* Complete Freund' s Adjuvant (CPA) "Sigma" , code: F-5881;

* Mycobacterium tuberculosis K37RA {MT) Mnf : Difco, code:

231141;

* Sterile phosphate buffered saline; and * Sterile purified wate .

Healthy, nulliparous, non-pregnant female mice of the C57B1/6 strain were obtained. The animals we ghed about 17-20 g on arrival, and were approximately 7 weeks; of age. 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 . The mice were individually identified by markings on the body.

Experimental Procedure Induction of Active EAE vas induced on day 1 by the subcutaneous injection in the flanks at 2 injection sites, the encephalitogenic mixture (emulsion) consisting of HOG and commercial CPA containing 5 mg/mL Mycobacterium tuberculosis (MT) at a volume oi: 0.2 mL/mouse in the right flank of the animals.

The dose of the KOG and MT is 300 g/m se and 500 yg/mouse respectively.

Pertussis toxin was injected intra peritonealiy on the day of induction and 48 hours la e at dose level o£ 150 ng/0,2 will/mouse .

The mice were allocated to the fo lowing treatment groups mice/group) :

Table ["reatraent Gxxmps

A -moming; P -evening.

Pr&parstion and adminis ratio o£ encaph&lito enio emulsio ; Oil portion: CPA (containing 5 mg/ml MT) .

Liquid portion; 85.5 mg MOG was dissolved in 28.5 tuL Normal saline to yield 3 mg/mL MOG.

Emulsion: The emulsion was; made from equal parts of oil (28.5 n\L CPA containing 5.0 rag/mL MT) and liquid portions (785. S mg OG/28.5 !tiL PBS) in 2 syringes connected to each other with Leur lock. The concentration of MOG in emulsion was 1.5 mg/xitL. The emulsion w s transferred to insulin syringe before injection. 0,2 mL of 1.5 rag/mL MO emulsion were injected sc into flanks at 2 injection sites equivalent to 0.3 tp.g MOG/0.2 mL/mouse , epara ion and ad inistratio of Per ussis toxins

85 uL Pertussis toxin (200 pg/mL) was added to 22.58 saL PBS to yield 750 ng/mL,

The pertussis toxin was administered intravenous on the day of encephalitogen injection and 48 hours later (150.0 ng/0 , 2 mL/mouse X 2-300 ng/ ouse) .

Pr@para.tian and dministration o£ fcest a ticles f Rolipram formulat ions .-

Formulations of Rolipram were prepared daily in 0.5% Methocel/HjO.

Concentra ions of 0.5 aig/mL (groups 4 and 6) and 1 mg/ml (groups 5 and 7) were prepared for dose levels of 5 and 10 mg/kg bid (see Table i ) .

Laminimod formulations .* Concentration of 0,5 and 2.5 mg/roL laquinimod were prepared in 0.5% Methocei . The test formulations were stored at 2-8 C until use in atnber colored bottles for not more than 8 days.

The mice were administered an oral dose {gavage} from day 1,· once daily iqd) with concen ations of laquinimod of 0.5 or 2.5 rag/mL a volume dose level of 200 pL/tnouse by the oral route for a dose levels of 5 (groups 2, 6., and 7} or 25 rrig/kg (group 3) according to experimental design in Table 1 ,

Morbidity and Mortalityz

All animals were examined once daily to detect if any were dead or moribund,

E&E Clinia&l Sign®,-

Scoring of EAE clinical signs was initiated on the 10 ^l day post- ΕΆΕ induction and continued daily for 30 days.

The clinical signs wex-e recorded on observation cards according to a grading system described in 2.

Table 2: Evaluation of the EAE Clinical Signs

All mice having scores o£ 1 and above are considered s;ick.. A imals with score 5 for more than 3 days are given score S and sacrificed for humane reasons . For calculation purposes, the score i6) of animals that are sacrificed or died is carried forward.

Data Analysis and Calculations

Acceptance Cr£t®ri& for E&E Induced eg&tiv® Control group;

The control group should have at least 70% incidence. The MMS should he more than 2.0.

Calculation of the incidence of disease (Disease ratio) ι The number of sick animals in each group were summed. The incidence of disease was calculated as f No. of sick mice in treated group )

INCIDENCE of DISEASE = 2 t~

No. of sick mice in control group )

The percent inhibition according to incidence was calculated as

( , Number of sick mice in treated group .„_Λ

INHIBITION (%)e>/ INCIDENCE « 1 - ···- ····· xlUO

^ Number of sick mice in control group J

Calculation of tha ari&li y/moribi dity rat® (mortality ratio) s The number of dead or moribund animals in each group were

The mortality of disease was calculated as

_ .„, , , ,„ I No. of dead or moriboimd mice in treated group )

MORTALITY oj DISEASE ·· _: ;;^:·· ··· I

^ No. of dean or moriboimd mice in control group J The percent inhibition according to mortal y was calculated as . Number of dead or moriboimd mice in treated group

INHIBITION (%) of MORTALITY χϊΟΟ

\ Number of dead or moribound mice in control group )

Calculation of du a ion of diasas&i The mean, duration of disease expressed in days was calculated a

'∑ Duration of disease of each moused

Mean Durainon -i " ^:' i

_ No. of mice in ih e group j

Calculation of snaan dol&y in o s t o£ dis@&B&t

The mean onset of disease ex ressed in days was calculated as f∑ Onset of disease of each mouse \

Mean Onset ~

No. of mice in ih srouo

The onset of disease fior a mouse that, did not develop EAE is considered as 31 days (one day after termina ion of study) . The mean delay in onset of disease expressed in days was calculated by subtracting the mean onset of disease in control group from teat grou .

C&lGul&tion of th@ e&zi ascims,! &aor@ and a c t inhibitions The mean maximal score {MMS ) of each group was calculated as

! I Maximal Score of eaeh mouse

MMS

No. of mice in h e group

The percent, inhibition according to MMS was calculated as

The daily scores of each mouse in the test group were sutnmed and the individual mean daily score (IMS) was calculated as

,,_»-, ί ∑ Dsilv score of mouse

^ Observation period [days) } The mean group score (GMS) was calculated as

( ∑ IMS of ea ch mouse )

\ No. of mice m t group j The percent inhibition was calculated as

! GMS of treated groan )

INHIBITION (%)ofGMS = 1~ - OO

! GMS of control group }

Results

A summary of the incidence,, mortality, Group Mean Score (GMS) , duration of the disease, onset of the disease and the activity of each group compared to the vehicle treated control group is shown in the Summarised Table 3. The Clinical profile of Che treatment groups are presented graphically in Figure 1.

Table 3: Summary Tessi: Results: Test Articles: Laquinimod and Rolipram: Mortality, Incidence, MMS, GMS , Duration, Onset,, and SAE Inhibition Compared to Vehicle,

MO T: Mortality

INC: Incidence

Ϊ. Η : Inhibition

{¾ ciu i∞ on Rolipram at dose level of 10 mg kg when combined wit laquxnimod at dose level of 5 mg/kg exhibited additive effect expressed by- greater activity according to Incidence,, MMS, GMS, onset and Duration of KAE in group created with combination of laquxnimod {5 mg/kg) and Rolipram {10 mg/kg) compared to each tested alone .

Rolipram and Laquinimod to Mice

Stud_Dssign

3 groups of mice :

1. Rolipram 10 mg/kg 2. Laquxnimod 5 rag/kg

3. Rolipram 10 mg/kg and lagui nimod 5 mg/kg . Blood sampling at: 0.25, 0.5, 1, 2, 4 and Sh, n»2 per time point. Results

Mean maximal plasma concentration of Rolipram was increased following co-adtainist r tion with Laquxnimod. Mean exposure of Laquxnimod was decreased following co -administration with Rolipram JLf^'-G-L_. ° f Laquxni od on Rolipram PK Pro i.1e i ___?iice

See Figure 2. Effect: of Roli ram on &=* ^ϋ1¾^Ί12ί1^ See Figure 3.

* Laq initnod had a low to moderate effect on maximal plasma concentration of Rolipram when co-administered with

Laquinimod,

• Rolipram decreased total exposure of Laquinimod when co- administered with Laquinimod.

EXAMPLB 3; Assessment of Efficacy of Laquinimod As Add-On Therapy To PDE4 Inhibitors In Multiple Sclerosis (MS? Patients

Periodic oral administration of laquinimod as an add-on therapy for a human patient afflicted with a form of MS who is already receiving a PDE4 inhibitor as described herein provides a clinically meaningful advantage and is more effective (provides at least an additive effect, or more than an additive effect) in treating the patient than when the PDE4 inhibitor is administered alone {at the same dose) .

Periodic oral administration of a PDE4 inhibitor as described herein as an add-on therapy for a human patient afflicted with a form of KS who is already receiving of laquinimod provides a clinically meaningful advantage and is more effective (provides at least an additive effect or more than an add ive effect? in treating the patient than when laquinimod is administered alone (at the same dose) . The add-on therapies also provides efficacy (provides at least an additive effect or more than an additive e ect) in treating the patient without undue adverse side effects or affecting the safety of the treatmen . As compared to when each agent is administered alone: 1. The add-on therapy is more effective (provides an additive effect or more than an additive effect) in reducing the decrease in brain volume (determined by the percent, brain volume change (PBVC) } , in multiple sclerosis patients.

The add-on therapy is more effective ⁽provides an additive effect or more than an additive effect) in increasing the time to con irmed disease progression (CDF) , in multiple sclerosis patients, where CDP is defined as a sustained increase in EDSS of >1 point from Baseline for at least 3 months. Progression cannot he confirmed during a χ-elapse. he add-on therapy is more effective (provides an additive effect or more an an additive effect) in reducing abnormalities observed in whole Brain M R histogram, in multiple sclerosis patients.

The add-on therapy is more effective (provides an additive effect or more than an additive effect) in reducing the number of confirmed relapses and there Sore the relapse rate,, in multiple sclerosis 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. multiple sclerosis patients, as measured by the time to confirmed progression of EDSS.

The add-on therapy is more effective (provides an additive effect or more than an additive effect) in reducing M I- monitored disease activity in multiple sclerosis patients, as measured by the cumulative number of: Tl Gd~enhancing lesions on Tl -weighted images, the cumulative number new Tl hypointense lesions, the cumulative xjumber of new T2 lesions, the cumulative number of new Tl hypointense lesions on Tl- weight images (black: holes) , the number of active (new T2 or GdE-Tl) 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. 7. The add-on therapy is snore effective (provides n additive effect or more than an additive effect; in reducing brain atrophy in multiple sclerosis patients.

8. The add-on therapy is more effective {provides an additive effec or more than an additive effect) in reducing the frequency of relapses, the frequency of clinical exacerbation, and the risk for confirmed progression in multiple sclerosis patients.

3. The add-on. therapy is more effective (provides an additive effect or more than an additive effect) in increasing the time to confirmed relapse in multiple sclerosis patients.

10. The add-on therapy is more effective {provides an additive effect or more than an additive effect) in improving the general 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 multiple sclerosis patients .

11. The add-on therapy is more effective (provides an additive effect or more than an additive effect) in decreasing cerebral dysfunction/cogn ive impairment (as assessed by Symbol Digit Modalities Test iSDMT) ) , in multiple sclerosis patients during the double bl nd study period.

Administration of laquiniutod as an add-on therapy to a PDE4 .inhibitor as described herein 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 CIS suggestive of MS than when, the PDE4 inhibitor is administered alone (at the same dose} .

Administration of laquiniraod as an add-on therapy to a PDE4 inhibitor as described herein 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 o£ clinically definite MS, the occurrence of new MRI -detected lesions in the brain,, the accumulation of lesion area in Che 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 Chase persona than when the PDE4 inhibitor is administered alone {at the same dose) .

Administration of a PDE4 inhibitor as described herein as an add- on therapy to laquinimod 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 CIS suggestive of MS than when laquinimod is administered alone {at the same dose) . Administration of a PDE4 inhibitor as described herein as an addon therapy to laquinimod provides a clinically meaningful advantage arid, is mo e 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 occurrence of clinically definite MS and preventing irreversible brain damage in these persons than when laquinimod is administered alone (at the same dose) .

EXAMPLE 4 : A.sses ment of Sffic cy of Laquinimod In Combination With A FDE4 Inhibitor In Multiple Sclerosis (MS) Patients

Periodic oral administration of laquinimod in combination with a PDE4. inhibitor as described herein to a human patient afflicted with relapsing form of multiple sclerosis provides increased efficacy (provides at least, an additive effect or more than an additive effect) in treating the patient than when laquinimod is administered alone or when the PDB4 inhibitor is administered alone (at the same dose) , The combination therapy also provides efficacy (provides at least, an additive effect or more than an additive effect) in treating the patient without undue adverse side effects or affecting the safety of the treatment .

The combination therapy provides; a clinically meaningful advantage and is more effective {provides at least an additive effect or more than an additive effect) in treating the patient than when laquiaimod or the P E4 inhibitor is administered alone (at the same dose) in the following manner:

1. The combination therapy is more effective (provides an additive effect or more than an additive effect) in reducing the decrease in brain volume (determined by the percent brain volume change (PBVC) ) , in multiple sclerosis patients.

2. The combination therapy is more effective (provides an additive effect or more than an additive effect) in increasing the time to confirmed disease progression (CD?) , in multiple sclerosis patients, where CDP is defined as a sustained increase in EDSS of >1 point om Baseline for at. least 3 months. Progression cannot be confirmed during a relapse ,

3. The combination therapy is more effective (provides an additive effect or more than an additive effect) in reducing abnormalities observed in whole Brain. MTR histogram; in multiple sclerosis patients during.

4. The combination therapy is more effective (provides an additive effect or more than an additive effect) in reducing the number of confirmed relapses and therefore the relapse rate,, in multiple sclerosis patients .

5. The cafiibination therapy is also more effective {provides an additive effect or more than an additive effect) in reducing the accumulation of physical disability in multiple sclerosis patients,, as cm?,assu ed by the time to confirmed progression of EDSS . The combination therapy is more effective {provides an additive effect or more than an additive effect) in reducing M I-monitored disease activity in multiple sclerosis patients., as measu ed by the cumulative number of Tl Gd~enhancing lesions on Tl -weighted images, the cumulative number new Tl hypointense lesions, the cumulative number of new T2 lesions, the cumulative number of new Tl hypointense lesions on T2 -weight images (black holes) , the number of active {new T2 or GdE-TI) 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 combination therapy is more effective {provides an additive effect or more than a additive effect} in reducing brain atrophy in multiple sclerosis patients.

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 multiple sclerosis patients,

The combination therapy is more effective (provides an addi ive effect or more than an additive effect) in increasing the time to confirmed relapse in multiple sclerosis patients .

The combination therapy is more effective (provides an additive effect or more than an additive effect) in improving the general health status {as assessed by the EuroQoL (SQ5D) questionnaire) , symptom severity on work (as assessed by the work productivity and activities impairment General Health ( PAI-GH) questionnaire) and quality of life, in multiple sclerosis patients.

The combination therapy is more effect ve (provides an additive effect or more than an additive effect) in decreasing cerebral dysfunction/ cognitive impairment (as assessed by Symbol Digit Modalities Test <SDMT) 5 _t in multiple sclerosis patients during the double blind study period .

Administration of laquinimod in combination with a PDS4 inhibitor as described herein provides a clinically meaningful advantage and is more effec ive {provides an additive effect or more than an additive effect} in delaying the conversion to clinically definite MS in patients presenting a CIS suggestive of K3 than when the PDS4 inhibitor is administered alone (at. the same, dose} . Administration of laquinimod in combination with a PDE inhibitor as described herein provides a clinically meaningful advantage and is more effective (provides an additive effect or more than an additive effect) in reducing the rats of development of clinically definite MS, the occurrence of new M I -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 occurrence of clinically definite MS and preventing irreversible brain damage in these persons than when the PDE4 inihibtor is administered alone (at the same dose) .

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Claims

What is claimed iss

1. A method of treating a sub ect afflicted with multiple sclerosis (MS) or presenting a clinically isolated syndrome (CIS) comprising administering to the subject: an amount of laquinimod and an amount of a phosphodiesterase Type 4

(FDE45 inhibitor.

2. The method of claim I, comprising periodically administering to tha subject an amount of laquinimod and an amount of the PDE4 inhibitor,, wherein the amount of laquinimod and the amount of the P .E4 inhibitor when taken together is mo e effective to treat the subject than when each agent at the same respective amount is administered alone.

3. The method of any one of claims 1 or 2, wherein, the MS is relapsing MS,

4. The inethcd of claim 3, wherein the relapsing MS is relapsi g-remi tting MS .

5. The method of any one of claims 1-4.. wherein the amount, of laquinimod and the amount of the PDE4 inhibitor when taken together is effective to reduce a symptom of MS in the subject .

S. The method of claim 5, whexrein the symptom is a MRI-monitored MS 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 apoptosis, risk for confirmed progression, deter oration. of

function, fatigue, impaired mobility, cognitive impairment, reduction of brain volume, abnormalities observed in whole Brain MTR histogram., deterioration in general health status, functional status, quality of life, and/or symptom severity on work.

7. The method of claim 6, wherein the amount of laquinirood and the. amount of the PDK4 inhibitor when taken together is effective to a) decrease or inhibit reduction of: brain, volume, b) increase time to confirmed disease progression, decrease abnormal ties observed in whole Brain MTR histogram,, or d; reduce cognitive impairment .

8. The method of claim '7, wherein brain o um is measured by percent brain volume change (PBVC) .

9. The method of claim 7, wherein time to confirmed disease progression is increased by 20-60%.

10. The method of claim 7, wherein cognitive impairment is assessed by the Symbol Digit Modalities Test {SDMT) score.

11. The method of claim 6, wherein the accumulation of physical disability is measured by Kurtzke Expanded Disability Status Scale (B SS5 score, or is assessed by the time to confi raed disease progression as measured by EDSS score.

12. The method of claim 6, wherein the subject had an EDSS score of 0-5.5 at baseline, an EDSS score of 1.5-4.5 at baseline or an EDSS score of 5,5 or greater at baseline,

.13, The method of claims II or 12, wherein confirmed disease progression is a 1 point or a 0,5 point increase of the EDSS s o ,

14. The method of claim 6, wherein impaired mobility is assessed by the Timed- 25 Foot Walk test, the .12 -Item MS Walking Scale (MS S-12) self-report questionnaire, the Ambulation Index (ΆΙ5 , the Six-Minute Walk Test or the Lower Extremity

Manual Muscle Test (LEM T) Teat. The method of claim 6, wherein general health status is assessed by the E roQoL (EQ5D) questionnaire, Subjec Global Impression (SGI) or Clinician Global Impression of Change CCGIC) .

The method of claim 6, wherein Hunctional status is measured by the subject's Short-Form General Health survey (SF-36; Subject Reported Questionnaire score.

The method of claim S, wherein quality of life is assessed by SF-36, SQ5D, Subject Global Impression (SGI) or Clinician Global Impression of Change (CGIC) .

The method of claims IS or 17, wherein, the subject's SF-36 mental component summary score (MSG) is improved.

The method of any one of claims 16-18, wherein the subj ect ' 8 SF-36 physical component summary sore (PSC5 is improved.

The method of claim 6, wherein fatigue is assessed by the EQ5D, the subject's Modified Fatigue Impact Scale (MPIS) score or the French valid versions of the Fatigue Impact Scale (E IF-SE?) score.

The method of claim 6, wherein symptom severity on work is; measured by the work productivity and activities impairment General Health (WPAI-GK) questionnaire.

The method of any one of claims 1-21, wherein laquinimod is laquinimod sodium.

The method of any one of claims 1-22, wherein the PDE4 inhibitor is rolipram., roflumilast .. cilomiiast, apre ilast, or d.iocl in.

The method of any one of claims 1-23, wherein the laquinimod and/or the PDE4 inhibitor is administered via oral administration ,

The method of any one of claims 1-30,. wherein the laquinimod and/or the ΡΏΕ4 inhibitor is administered daily. The method of any one of claims 1-25, wherein the iaquinimod and/or the PDH4 inhibitor is administered more often than once daily or less often than once daily.

The method of any one of claims 1-26, wherein the amount of laquinitnod administered is less than 0.6 ntg/<-

28. The method of any one of claims 1-26, wherein the amount of: laquinimod administered is 0.1-40.0 mg/day.

29. The method of claim 28, wherein the amount of laquinimod administered is 0.1-2.5 mg/day.

30. The method of claim 28, wherein the amount of laquinimod admin stared is 0.25-2,0 tag/day .

31. The method of claim 28, wherein the amount of laquinimod administered is 0.5-1.2 mg/day.

32. The method of claim 28, wherein the amount of laquin.itp.od administered is 0.25 mg/day, 0,3 mg/day, 0.5 mg/day, 0.6 rag/day, 1,0 mg/day, 1,2 mg/day, 1.5 tag/day, 1.8 mg/day or 2.0 mg/day.

33. The method of any one of claims 1-32, wherein the amount of the PDE4 inhibitor administered is 0.1-100 mg/day.

34. The method of claim 33, wherein the amount, of the PDE inhibitor administered is 0.5-60 mg/day.

35. The method of claim 34, wherein the amount of the PDE4 inhibitor administered is about 0.5, 1.0, S.O., 10.0, 15.0, 20.0, 25,0 30.0.. 40.0, 50.0, or SO.O mg/day,

36. The method of claim 35, wherein the amount of the PDE4 inhibitor administered is 0.5, 1.0, 5.0, 10.0, 15.0, 20.0, 25.0,. 30.0, 40.0, 50,0, or 60.0 mg/day,

37. The method of any one of claims 2-36, wherein a loading dose of an amount different from the intended dose is administered for a period of time at the start of the periodic administra ion of at least one of laquinimod and the PDE4 inhibitor, 8, The method of any one of claims 1-37, wherein the subject is receiving laquinimod therapy prior to initiating the PDE4 inhibitor therapy . $. The method of any one of claims 1-37, wherein the sub ect is recei ing the PDE4 inhibitor therapy prior to initiating laquinimod therap . 0, The method of claims 38 or 39, where in the subject is receiving a fi st therapy for at least 8 weeks., at least 10 weeks , at least 24 weeks, at least 28 weeks, at leas;: 43 weeks or a.t least 52 weeks prior to initiating a second therap . 1, The method of any one of claims 1-40, further comprising administration of nonsteroidal ant - inflammatory drugs {NSAIDs) , salicylates, slow-acting drugs, gold compounds , hydroxych oroquine , sulfasalasine , corticost roids , cytotoxic drugs, immunosuppressive drugs and/or antibodies. 2, The method of any one of claims 1-41, wherein the periodic administration of laquinimod and the PDE4 inhibitor continues for at least 3 days, for more than 30 days, for more than 42 days, for 8 weeks or mors, for at least 12 weeks, for at least 24 weeks or for 6 months or more , 3, The method of any one of claims 1-42, wherein the administration of laquinimod and the PDE4 inhibitor inhibits a symptom of relapsing MS by at least 20%, by at least 30%, by at least 50%, by at least 70%, by more than 100%, by more than 300% or by more than 1000%, 4, The method of any one of claims 1-43, wherein each of the amount of laquinimod when taken alone, and the amount of the PDE4 inhibitor when taken alone is effective to treat the subjec , The method of any one of claims 1-43, wherein either the amount of lacjuirdnrad wh n taken alone, the amount: of the PDE4 inhibitor when taken alone, or each such amount when taken alone is not effective to treat the subject.

The method of any one of claims 1-45, wherein the subject is a human patient.

A package comprising: a) a first. pharmaceu ical composition comprising an amount of laquinimod and a pharmaceutically acceptable car ier ; b} a second pharmaceutical composition comprising an amount of a PDE4 inhibitor and a pharmaceutical ly acceptable carrier,* and c) instructions for use of the first and. second pharmaceutical compositions; together to treat a subject, afflicted with MS or presenting a CIS,

The package of claim 47, wherein the first pharmaceutical composition, the second pharmaceutical composition,, or both the first and the second pharmaceutical compositions are in an aerosol, an inhalable powder, ars injectable, a liquid, a solid, a capsule or a tablet form.

The package of claim 48, wherein the first pharmaceutical composition, the second phartnaceutical compos ion, or both, the first and the second pharmaceutical compositions are in a liquid or a solid form.

The package of cl im 49, wherein the first pharmaceu ical composition, the second pharmaceutical composition, or both the first and the second phartnaceutical compositions are in capsule form or in tablet form.

The package of claim 50, wherein the tablets are coated a coating which inhibits oxygen from contacting the core 52, The package of claim 51, wherein the coating comprises a cellulosic polymer, a detackifier, a gloss enhancer, or pigment .

53. The package of any one of claims 47-52, wherein the first pharmaceutical composition further comprises mannitol, an alkalinizing agent , an oxidation reducing agent, a lubricant, and/or a filler.

54, The package of claim 53, wherein the alkalinizing agent is meglumine .

BB - The package of claims 53 or 54, wherein the lubricant is present in the composition as solid particles.

56. The package of any one of claims 53-55, wherein the lubricant is sodium stearyl fumarate or magnesium stearate.

S? . The package of any one of claims 53- 56, wherein the filler s present in the composition as solid particles.

58, The package of any one of claims 53-57, wherein the filler is lactose, lactose monohydrate , starch, isoma It, mannitol , sodium starch, glycolate, sorbitol, lactose spray dried, lactose anhydrous© , or a combination thereof.

55. The package of claim 58, wherein the filler is manni ol or lactose monohydrate .

SO. The package of any one of claims 47-59, wherein the first pharmaceutical composition is stable and free of an alkalinizin agent or an oxidation reducing agent.

61, The package of claim SO, wherein the first pharmaceutical composition is free of an a kalinising agent and free of an oxidation reducing agent.

62... The package of any one of claims 47-61, wherein the first pharmaceutical composition is stable and free of disintegran . The package of any one of claims 47-62, further comprising a desiccant »

The package of claim 63, wherein the desiccant is silica gel.

The package of any one of claims 47-64, wherein the first pharmaceutical composition is stable and has a moisture content of no more than. 4% .

The package of any one of claims 47-65, wherein laquinimod is present in the composition as solid particles.

The package of any one of claims 47-66, wherein the package is a sealed packaging having a moisture permeability of not more than .15 mg/day per liter.

The package of any one of claim 53-67, wherein the sealed package is a blister pack in which the maximum moisture permeability is no more khan 0.005 mg/day.

The package of claim 68, wherein the sealed package is a bottle and/or comprises an HO E bottle .

The package of claim 69, wherein the bottle is closed with a heat i duction iiner .

The package of any one of claims 67-70, wherein the sealed package comprises an oxygen absorbing agent.

The package of claim 71, wherein the oxygen absorbing agent is i on.

The package of any one oil claims 47-72, wherein the amount of laquinimod in the first composition is less than 0.6 mg.

The package of any one of claims 47-72, wherein the amount of laquinimod in the firs;: composition is 0.1-40,0 mg.

The package of claim 74, wherein the amount of laquinimod is 0.1-2.5 mg. The package of claim 7 , wherein the amount of laquinimod is 0.25-2.0 rag.

77. The package of claim 74, wherein the amount of laquinimod is 0.5-1.2 rag ,

78. The package of claim 74, wherein, the amount of laquinimod is 0,25 H\g , 0,3 mg , 0,5 mg , 0. S mg , 1.0 mg , 1.2 rag , 1,5 mg or 2 , 0 mg .

79. The package of any one of claim 47-78, wherein the amount of the PDS4 inhibitor is 0,1-100 rag.

80. The package of claim 79, wherein the amount of the PDE4 inhibitor is 0,5-SO nig.

81. The package of claim SO, wherein the amount of the PDE4 inhibitor is about 0.5, 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 30.0, 40.0, 50,0, or 60.0 mg.

82. The package of claim 81, wherein the amount of the PDE4 inhibitor is 0.5, 1.0, 5.0, 10,0, 15.0, 20.0, 25.0, 30,0, 40,0, 50,0, or 60.0 mg,

83. The package of any one of claims 47-82, wherein the amount o Laquinimod and. the amount of the PDE4 inhibitor are prepared to be administered simultaneously, contemporaneously or concomitantly.

84. A therapeut c package for dispensing to, or for use in dispensing to, a subject afflicted with MS or presenting a

CIS, which comprises: a} ne or more unit doses, each such unit dose comprising: i] an amount of laquinimod and i:i. } an amount, of a P E4 inhibitor wherein the respective amounts of said laquinimod and said PDS4 inhibitor in said unit dose are effective, upon, concomitant administration to said sub ect, to treat the subject , and b) a finished pharmaceutical container therefor, said container containing said unit dose or unit doses, said container further containing or comprising labeling directing the use of said package in the treatment of said subject.

The therapeutic package of claim 84,. wherein the respective amounts of said laquinimod and said PDB4 inhibitor in said unit dose when taken together is more effective to treat, the subject than when compared to the administration of said laquinimod in the absence of the PDE4 inhibitor or the administration of the PDS4 inhibitor in the absence of said laquinimod.

The therapeutic package of claims of claims 84 or 85, wherein the P E4 inhibitor is rolipram, roflumilast, cilomilasc, apremilast, or dioclein.

A pharmaceutical composition comprising an amount of laquinimod and an amount of a PDE4 inhibitor.

The pharmaceutical composition of claim 86,. consisting essentially of an amoun of laquinimod and an amount of a PDS4 inhibitor.

The pharmaceu ical composition of claims 87-88 for use in treating a subject afflicted with MS or presenting a CIS, wherein the laquinimod and the PDS4 inhibitor are prepared to be administered simultaneously, contemporaneously or concoKii;:antly.

The pharmaceutical composition of any one of claims 87-89 wherein laquinimod is laquinimod sodium.

The pharmaceutical composition of any one of claims 87-90, wherein the PDE4 inhibitor is rolipram, roflumilast, c lomilast, apremilast, or dioclein. 92, The pharmaceutical composition of any one of claims 87-91, in an aerosol, an inhalabie powder, an inj actable, a liquid, a solid, a capsule or a tablet form,

93, The pharmaceutical composition of claim 92, wherein the tablets are coated with a coating which inhibits oxygen from contacting the core ,

94, The pharmaceutical composition of claim 93, wherein the coating comprises a cell losic polymer, a detackifier, a gloss enhancer, or pigment,

95, The pharmaceutical composition of any one of claims Θ7-94, further comprising mann oi , an alkal n zing agent., an oxidation reducing agent, a lubricant or a filler.

96, The pharmaceutical composition of claim 95, wherein the alkalxnizing agent is meglumine .

97, The pharmaceutical compos tion of claims 95 or 96, wherein the lubricant is present in the composition as solid par icles .

98, The pharmaceutical composition of any one of claims 95-97, wherein the lubricant is sodium stearyl fumarate or magnesium stearate.

99, The pharmaceutical composition oil any one of claims 95-98, wherein the filler is present in che composition as solid particles .

100 , The pharmaceutical compositio of any one of claims 95-99, wherein the filler is lactose, lactose monohydrafce, starch, isomait, mannitoi, sodium starch glycolate, sorbitol, lactose spray dried, lactose anhydrouse, or a combination thereof .

101, The pharmaceutical composition of claim 100, wherein the filler is mannitoi or lactose onohydra e.

102. The pharmaceutical composition of any one of claims 87-101, which is free of an lkaiinising agent or an oxidation reducing agent .

103. The pharmaceutical composition of claim 102,. which is free of an alkal niisiag agent and free of an oxidation reducing agent ,

104. The pharmaceutical composition of any one of claims 87-103, which is stable and free of dieintegrant .

105. The pharmaceutical composi ion of any one of claims 87-104, wherein the amount of laquinimod in the composition is less than 0.6 nig .

106. The pharmaceutical composition of any one of claims 87-104, wherein the amount of laquinimod in the composition is 0.1- 0.0 mg ,

107. The pharmaceutical composition of claim 106, wherein the amount of laquinimod is 0.1-2.5 mg,

108. The pha maceutical composition of claim 106, wherein the amount of laquinimod is 0,25-2,0 mg.

109. The pharmaceutical composition of claim 106, wherein the amount of l quinimod is 0.5-1.2 mg.

110. The pharmaceutical composition of claim 10S, wherein the amount, of laquinimod is 0.25 mg,. 0.3 mg, 0.5 rag, 0.S mg, 1,0 mg, 1 , 2 Rig, 1 , 5 mg, 2.0 mg .

111. The pharmaceutical composition of any one of: claim 87-110, wherein the amount of the PDS4 inhibitor is 0.1-100 mg.

.112. The pharmaceutical composition of claim 110, wherein the amount of the PDE4 inhibitor is 0.5-60 mg.

113. The pharmaceutical composition of claim 110, wherein the amount of the PDE4 inhibitor is about 0.5, 1.0, 5,0,. 10.0, 15.0, 20,0, 25,0, 30.0, 40,0, 50,0, or 60.0 mg.

114. The pharmaceutical composition of claim 110, wherein the amount of the P E4 inhibitor is 0,5, 1.0, 5.0, 10.0,, 15.0, 20.0, 25.0, 30.0, 40.0, 50.0, or 60.0 mg.

115. A pharmaceutical composition in unit dosage form, useful in treating a subject afflicted with MS or presenting a CIS, which comprises; a) an amount of laquinimod; b) an amount of a PDE ixj ibitor, wherein the respective amounts of said laquinimod and said PDE4 inhibitor in said composition are effective, upon concomitant administration to said subject of one or more of said unit dosage forms of said composition, to treat the s b ect .

I S. The pharmaceutical composition of claim 115, wherein the respective amounts of said laquinimod and the PDE4 inhibitor in said unit dose when taken, together is more effective to treat the subject, than when compared to the administration of said laquinimod in the absence of the PDE4 inhibitor or the administration of the PDE4 inhib tor in the absence of said laquinimod.

117. A pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with MS or presenting a CIS as an add-on therapy or in combination with a PDE4 inhibitor.

118. A pharmaceutical composition comprising an amount of laquinimod for use in treating a subject afflicted with MS or presenting a CIS simultaneously, contemporaneously or concomitantly with a PDE4 inhibitor.

119. A pharmaceutical composition comprising an amount of a PDE4 inhibitor for use treating a subject afflicted with MS or presenting a CIS as an add-on therapy or in combinat on with .la ui im .

120. A pharmaceutics 1 composition comprising an amount of a PDE4 inhibitor for use creating a subject afflicted with MS or presenting a CIS simultaneously, contemporaneously or concomitantly with laqu nimod.

121. Laquiaimod for uss as an add-on therapy or in combination with a PDE4 inhib tor in treating a subject afflicted with MS or presenting a CIS.

.1.22. A PDE4 inhibitor for use as an add-on therapy or in combination with laquinimod in treating a subject afflicted with MS or presenting a CIS.,

123. Use of an amount of laquinimod and an amoun of a PDS inhibitor in the preparation of a combination for treating a subject afflicted with MS or presenting a CIS wherein the lag iniraad and the PDE4 inhibitor are prepared to be administered simultaneously, contemporaneously or concomitantl .

124. The pharmaceutical composition of any one of claims 115-12Q, or the use of any one of claims 121 -123, wherein the PDE4 inhibitor is rolipram, rofluroilast, eilomilast, apretailast, or dioclein.