GB2540163A

GB2540163A - Combination therapy for treating multiple sclerosis

Info

Publication number: GB2540163A
Application number: GB1511895.3A
Authority: GB
Inventors: Schmierer Klaus; Baker David
Original assignee: Queen Mary University of London
Current assignee: Queen Mary University of London
Priority date: 2015-07-07
Filing date: 2015-07-07
Publication date: 2017-01-11
Also published as: GB201511895D0

Abstract

The invention provides a combination therapy for the treatment of multiple sclerosis (MS) in a subject in need thereof comprising administering cladribine and laquinimod. The cladribine and/or the laquinimod may be administered orally, intravenously or subcutaneously. However, it is preferred that both the cladribine and the laquinimod are administered subcutaneously. The cladribine and the laquinimod may be administered simultaneously. Alternatively, the administration of cladribine precedes the administration of laquinimod or the administration of laquinimod precedes the administration of cladribine. More preferably, the administration of cladribine and laquinimod continues for more than 30 days. In another aspect, a pharmaceutical composition comprising cladribine or a pharmaceutically acceptable salt or hydrate thereof, and laquinimod or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of MS. The composition may comprise a carrier and the laquinimod may be present as laquinimod sodium.

Description

Combination therapy for treating multiple sclerosis

Field of the invention

The present invention relates to compositions and methods for the treatment of people with multiple sclerosis (pwMS).

Background

Multiple sclerosis (MS) is a chronic disease characterized by focal inflammatory demyelination and neurodegeneration of the central nervous system. It is one of the most common neurological diseases with most patients diagnosed between the ages of 20 and 40. It is estimated that MS affects over 120,000 people in the United Kingdom alone and over 2.5 million worldwide. The symptoms of MS vary both from person to person and day to day and can include dizziness, fatigue, loss of vision and/or hearing, double vision, muscular weakness, numbness, spasms, tremors, pain, loss of balance, loss of muscle control, trouble breathing and swallowing, uncontrolled eye movements, trouble chewing and speaking, decreased attention span, poor judgment, memory loss, difficulty reasoning and solving problems and/or depression.

The disease can be fundamentally classified into relapsing and progressive MS (RMS, PMS). These phenotypes are then further divided into “active” and “non-active” disease, defined either clinically (active= occurrence of relapses or “flare-ups”) or on magnetic resonance imaging (MRI) (active= detection of new and/or enhancing lesions). People with PMS (pwPMS) are further categorized as currently (i.e. at the time of observation) undergoing clinically defined progression of disability or stable disease (with or without disease activity defined by relapses and/or new and/or enhancing lesions on MRI, as outlined above).

At first manifestation pwMS often present with a ‘clinically isolated syndrome’ (CIS) suggestive of demyelination. Over 80% of pwMS initially have RMS characterised by a flare-up of symptoms (relapses) followed by partial or full remission during which the symptoms are milder or disappear altogether. The remission period can last from a few days to a few months but is rarely permanent. Ten years after onset, approximately 50% of the people with RMS (pwRMS) will develop PMS, characterised by steady disease progression and accrual of disability. About 10% of pwMS have PMS from disease onset (primary progressive MS).

Less than 5% of patients with PMS at onset subsequently develop relapses with some degree of remission (progressive relapsing MS).

Although there are a number of disease modifying drugs on the market available for the treatment of MS, there is currently no cure. Evidence suggests an important role of auto-reactive T and B lymphocytes in MS pathophysiology. Cladribine is a synthetic purine analogue cytotoxic to lymphocytes, and to a lesser degree to monocytes and haematopoietic cells. As a result, cladribine induces a dose-dependent reduction of T and B cells lasting months to years. This lymphopenia is thought to underlie its therapeutic activity in pwRMS. Evidence from a large phase III trial (CLARITY) in pwRMS suggests cladribine is a highly effective disease modifying drug (DMD) with 45% of patients showing no evidence of disease activity (NEDA= no relapses, no disability progression, no new/enhancing lesions on MRI) after 96 weeks, following two courses of cladribine (Giovannoni et al. 2010 Barkhof F, etal. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009;5:256-66). This efficacy is comparable with the most effective DMDs licensed for pwRMS including the monoclonal CD52-specific antibody alemtuzumab (Cohen, et al. Lancet 2012; 380: 1819-28). ORACLE MS, another phase III study also found that cladribine significantly delayed MS diagnosis in CIS compared with placebo (LeistTP, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol 2014;13:257-67). Like cladribine, alemtuzumab can be an induction treatment given in two or more annual treatment cycles (Giovannoni et al. 2010). However, several adverse side effects have limited its use. Benign uterine leiomyomas and three cases of cancerwere noted in patients in the CLARITY study. Consequently, oral cladribine was refused a licence by the European Medicines Agency in 2013. There is therefore considerable prejudice in the art against the use of cladribine in the treatment of MS.

Laquinimod is an orally administered quinolone-3-carboxamide derived from linomide and is known to exert anti-inflammatory and neuroprotective effects. The mechanism of action of laquinimod is not fully understood but it appears to inhibit the infiltration of CD4+ T cells and macrophages into the CNS and to alter the cytokine profile via a shift from the Th1 to the Th2/Th3 phenotype (Yang et al, J Neuroimmunol 2004; 156:3-9). Although there are certain adverse effects associated with laquinimod - mainly elevated liver enzymes - the drug has been shown to be well tolerated in most cases.

The administration of two different drugs to treat a given condition raises a number of problems. Drug interactions are complex and hard to predict. Such interactions may alter the pharmacokinetics and clearance of one or more of the drugs being administered, and as such the intended dosage and expected efficacy of a drug may be altered, and in some cases contraindications may occur resulting in potentially serious or life-threatening adverse effects. In one example, combined administration of fingolimod and interferon (IFN) has been experimentally shown to abrogate the clinical effectiveness of either therapy. (Brod 2000) In another experiment, it was reported that the addition of prednisone in combination therapy with IFN-beta antagonized its up-regulator effect. Thus, when two drugs are 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.

In the case of cladribine and laquinimod it is not immediately apparent that a combination of these two drugs would result in a therapeutic effect with a favourable safety profile. As far as the inventors are aware, cladribine and laquinimod have not been used in combination for the treatment of multiple sclerosis.

Summary of the invention

The present invention is directed towards a method for treating people with CIS or multiple sclerosis in a subject comprising administering to said subject a therapeutically effective amount of cladribine and a therapeutically effective amount of laquinimod. The invention is also directed towards a pharmaceutical composition comprising cladribine and laquinimod for use in the treatment of multiple sclerosis.

Detailed description

In a first aspect the invention provides a method for treating multiple sclerosis in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of cladribine or a pharmaceutically acceptable salt or hydrate thereof and a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt or hydrate thereof.

As used herein, to "treat" or "treating" encompasses, for exam pie, inducing inhibition, regression, or stasis of, or ameliorating or alleviating a symptom of, a disease and/or condition. As used herein, "inhibition" of disease progression or complication in a subject means preventing or reducing relapses and/or deterioration (progression) of the disease and/or complication in the subject. "Ameliorating" or "alleviating" a condition or state as used herein shall mean to relieve or lessen the symptoms of that condition or state.

In an embodiment the subject is mammal. As used herein, the term “mammal” refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine or other veterinary or laboratory mammal. Those skilled in the art understand that the immune responses and immune pathologies of mammals share many common features, and that a therapy which reduces the severity of an immune pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal. The skilled person also appreciates that credible animal models of many human immune pathologies are known. For example, experimental autoimmune encephalomyelitis (EAE) is a credible animal model of human multiple sclerosis. In a preferred embodiment the subject is a human patient.

The term "therapeutically effective amount" as used herein means an amount effective, at dosages and for periods of time, necessary to treat the disease. As understood by one skilled in the art, the therapeutically effective amount is generally a function of a patient's age, sex, and physical condition, as well as a function of other concurrent treatments being administered. The determination of the optimum, therapeutically effective dosage is well within the scope of one skilled in the art.

In an embodiment of the invention the amount of cladribine is a therapeutically effective amount. That is, cladribine alone is able to have a therapeutic effect. In another embodiment, the amount of cladribine is not enough to show a therapeutic effect on its own, but a therapeutic effect is seen when used in combination with laquinimod.

In an embodiment of the invention the amount of laquinimod is a therapeutically effective amount. That is, laquinimod alone is able to have a therapeutic effect. In another embodiment, the amount of laquinimod is not enough to show a therapeutic effect on its own, but a therapeutic effect is seen when used in combination with cladribine.

In an embodiment of the invention the amount of cladribine is between 1mg and 50mg given daily for example, 1mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg or 50mg. In a preferred embodiment the amount of cladribine administered daily is 10mg. In an embodiment the pharmaceutical formulation is a pharmaceutical formulation described in WO 2004/087101 or in WO 2004/087100.

In another embodiment of the invention the therapeutically effective amount of laquinimod is between 0.1 mg and 40mg given daily for example 0.1 mg, 1mg, 2mg, 3mg, 4mg, 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg 0r40mg. In one embodiment, the amount laquinimod administered is less than 0.6 mg/day. In another embodiment, the amount laquinimod administered is 0.1-40.0 mg/day. In another embodiment, the amount laquinimod administered is 0.1-2.5 mg/day. In another embodiment, the amount laquinimod administered is 0.25-2.0 mg/day. In another embodiment, the amount laquinimod administered is 0.5-1.2 mg/day. In another embodiment, the amount laquinimod administered is 0.25mg/day. In another embodiment, the amount laquinimod administered is 0.3 mg/day. In another embodiment, the amount laquinimod administered is 0.5 mg/day. In another embodiment, the amount laquinimod administered is 0.6 mg/day. In another embodiment, the amount laquinimod administered is 1. 0 mg/day. In another embodiment, the amount laquinimod administered is 1. 2 mg/day. In another embodiment, the amount laquinimod administered is 1.5mg/day. In another embodiment, the amount laquinimod administered is 2.0 mg/day.

In one embodiment the invention provides a method for treating pwMS comprising administering cladribine to a subject according to the steps below - (i) An induction period wherein Cladribine is administered and wherein the total dose of Cladribine reached at the end of the induction period is from about 0.5mg/kg to about 5mg/kg 1.5 mg/kg to about 3.5 mg/kg; (ii) A Cladribine-free period wherein no Cladribine is administered; (iii) A maintenance period wherein Cladribine is administered and wherein the total dose of Cladribine administered during the maintenance period is lower than or equal to the total dose of Cladribine reached at the end of the induction period (i); (iv) A Cladribine-free period wherein no Cladribine is administered.

In another embodiment the invention provides a method for treating pwMS comprising administration of cladribine and laquinimod in combination, wherein cladribine is administered according to the steps below: (i) An induction period wherein Cladribine is administered and wherein the total dose of Cladribine reached at the end of the induction period is from about 0.5 mg/kg to about 5mg/kg; (ii) A Cladribine-free period wherein no Cladribine is administered; (iii) A maintenance period wherein Cladribine is administered and wherein the total dose of Cladribine administered during the maintenance period is lower than or equal to the total dose of Cladribine reached at the end of the induction period (i); (iv) A Cladribine-free period wherein no Cladribine is administered. whilst Laquinimod is administered as a once daily dose of between 0.1 mg and 40mg.

In an embodiment of the invention, the dosage protocol is as follows: A Cladribine

Week 1: Patients receive Cladribine 10mg scon three consecutive days.

Week 5: WBC will be obtained. Once results are available patients receive either NO further injections, OR - starting on the same day - up to three further injections: - If lymphocytes are >1 (x109): Cladribine 10mg sc will be given on three consecutive days. - If lymphocytes are 0.8-1 (x109): Cladribine 10mg sc will be given on two consecutive days. - If lymphocytes are 0.5-0.8 (x109): Cladribine 10mg sc will be given on one day. - If lymphocytes are below 0.5 (x109): NO further Cladribine will be given. B Laquinimod - Laquinimod given as a once daily dose of between 0.6mg and 1,5mg -On and after week 1, day 4 of cladribine administration except for those days where subsequent doses of cladribine are administered. - From week 1, day 1 of cladribine administration “Combination therapy” as used herein refers to administration of two or more compounds or compositions to a subject, for example cladribine or a pharmaceutically acceptable salt or hydrate thereof and laquinimod or a pharmaceutically acceptable salt thereof. In embodiments, the combination therapy may be administered simultaneously, sequentially or separately. In an embodiment of the invention, cladribine and laquinimod are administered simultaneously. Simultaneous administration maybe by means of a pharmaceutical composition comprising cladribine and laquinimod or by means of a pharmaceutical composition comprising cladribine and another pharmaceutical composition comprising laquinimod, both administered at substantially the same time. In another embodiment the cladribine and laquinimod are administered sequentially. In yet another embodiment, the cladribine and laquinimod are administered separately.

In a second aspect the invention provides a pharmaceutical composition comprising cladribine or a pharmaceutically acceptable salt or hydrate thereof, and laquinimod or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of multiple sclerosis.

Examples of pharmaceutically acceptable salts include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesutfonate and benzenesulfonate salts, or, when appropriate, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine. The compounds and salts of the methods of the present invention encompass hydrate and solvate forms.

In an embodiment of the invention the laquinimod is laquinimod sodium.

In an embodiment of the invention the pharmaceutical composition of the second aspect further comprises a pharmaceutically acceptable carrier. A "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the compounds to the intended subject.

In another embodiment the composition comprises a pharmaceutically acceptable excipient. Examples include, but are not limited to fillers, binders, lubricants and disintegrants. Excipients also include substances such as cellulose derivatives (e.g. hypromellose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose), polyvinylpyrrolidone, gelatin, lactose, sucrose, acacia, polyethylene glycol, polymethacrylates, hydroxypropylcellulose, pregelatinized starch and sodium alginate.

Examples of fillers include microcrystalline cellulose, powdered cellulose, compressible sugar, starch (e.g., corn starch or potato starch), pregelatinized starch, fructose, mannitol, dextranes, other sugars such as siliconized microcrystalline cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, tricalcium phosphate, calcium lactate or mixtures thereof. The fillers may be present in the form of a single compound or in the form of a mixture of compounds or co- processed compounds.

The compositions described herein may comprise binders such as cellulose derivatives (e.g. hypromellose, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose), polyvinylpyrrolidone, gelatin, lactose, sucrose, acacia, polyethylene glycol, polymethacrylates, hydroxypropylcellulose, pregelatinized starch and sodium alginate. The term "binder" as used herein is defined as an agent able to bind particles which cannot be bound only by a compression force. The binder may be present in the form of a single compound or in the form of a mixture of compounds.

The compositions described herein may comprise lubricants. Various suitable lubricants include but are not limited to stearic acid, talc, hydrogenated vegetable oil (e.g. hydrogenated castor oil), sodium lauryl sulphate, glyceryl behenate, polyethylene glycol, magnesium stearate, calcium stearate and sodium stearyl fumarate.

The compositions described herein may also comprise disintegrants. The term disintegrant as used herein is an agent accelerating the disintegration of the com position when in contact with a liquid. Preferred disintegrants are polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone (crospovidone), crosslinked sodium carboxymethyl cellulose, sodium carboxym ethyl starch, sodium carboxym ethyl glycolate and sodium bicarbonate. In one embodiment the composition is free of disintegrant.

Types of formulations:

The compositions disclosed herein can be administered orally, subcutaneously or intravenously. Oral formulations may be in the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binding agents, fillers, lubricants, disintegrants and wetting agents. Binding agents include, but are not limited to, syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch and polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, maizestarch, calcium phosphate, and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silica. Disintegrants include, but are not limited to, potato starch and sodium starch glycollate. Wetting agents include, but are not limited to, sodium lauryl sulfate). Tablets maybe coated according to methods well known in the art.

Compositions of this invention may also be liquid formulations including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs. The compositions may also be formulated as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain additives including, but not limited to, suspending agents, emulsifying agents, nonaqueous vehicles and preservatives.

Suspending agent include, but are not limited to, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxym ethyl cellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia. Nonaqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol. Preservatives include, but are not limited to, methyl or propyl p-hydroxybenzoate and sorbic acid. M-cresol may also be used as a preservative as well as the alkyl esters of para-hydroxybenzoic acid (the parabens, e.g. butylparaben, methylparaben and propylparaben), alone or in combination. Generally, the preservatives are used in a concentration of about 0.02% w/v.

The liquid formulation may also optionally contain a pharmaceutically acceptable buffer to maintain the pH at a range of about 5.5 to about 8.5. The preferred pH range for shelf stable solutions is about 6.0 and 8.0. Suitable buffers are any of those available for pharmaceutical application. Such buffers include but are not limited to phosphate, citrate, acetate, borate and tris. The preferred buffer for use herein is a sodium phosphate buffer system containing a mixture of monobasic sodium dihydrogenphosphate dihydrate and dibasic di-sodium hydrogenphosphate dihydrate. The ratio of phosphate buffers is adjusted to achieve the pH desired, generally in about a 2 to 1 monobasic to dibasic phosphate buffer ratio. The amount of buffer generally range from about 0 to about 12 mg/ml monobasic phosphate buffer and about 0 to about 24 mg/ml dibasic phosphate buffer.

An example liquid formulation of cladribine in the present invention may com prise the following composition (US6194395 B1):

Table 1

Monitoring the effect of treatment: A useful method of monitoring the effect of a treatment that potentially treats multiple sclerosis is magnetic resonance imaging, or MRI. As used herein, the term “magnetic resonance imaging” refers to conventional MRI methods, as well as improved magnetic resonance (MR) techniques, such as cell-specific imaging, magnetization transfer imaging (MTI), gadolinium (Gd)-enhanced MRI, proton magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), functional MR imaging (fMRI), and the other neuroimaging methods known in the art. MRI methods and their applications to MS are described, for example, in Rovaris etal, J. Neurol. Sci. 186 Suppl 1:S3-9 (2001) and Barkhof F, etal. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol 2009; 5:256-66. MRI techniques allow an assessment of the effects of treatment on amelioration of a variety of well-known indicia of MS, including oedema, blood brain barrier break-down, demyelination, gliosis, cellular infiltration, axonal loss, T2 lesion load, T1 lesion load, gadolinium positive lesion load, and the like.

In an embodiment the compositions and methods disclosed in the present invention are used to treat subjects presenting with clinically isolated syndrome (CIS) (Miller DH, et al. Differential diagnosis of suspected multiple sclerosis: a consensus approach. Multiple Sclerosis 2008; 14: 1157-74). “Clinically isolated syndrome" as used herein refers to 1) a single clinical attack (used interchangeably herein with "first clinical event" and 'first demyelinating 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 of a limb, lack of co-ordination, weakness of one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesia, burning sensations, muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of speech, slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, frequency, incomplete emptying and incontinence), bowel problems (including constipation and loss of bowel 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 third aspect the invention provides a kit for use in the treatment of multiple sclerosis. In an embodiment of the invention the kit comprises a first pharmaceutical composition comprising an amount of cladribine and a pharmaceutically acceptable carrier, a second pharmaceutical composition comprising an amount of laquinimod and a pharmaceutically acceptable carrier and instructions for use of the first and second compositions together to treat MS in a subject in need thereof. In a further embodiment the amounts of cladribine and laquinimod are therapeutically effective amounts. The kit may include a sealed container containing each composition of the invention separately or mixed together as a lyophilised powder and a second container containing a solvent. Further components may be included with the solid or liquid part. Thus the kit may com prise a first container containing the composition(s) and a second containing isotonic saline, or a first container containing the composition(s) and mannitol and a second container containing sterile water. Prior to administration the solvent is added to the container containing solid component in order to give the solution for injection.

Examples

Example 1: Administration schemes for cladribine and laquinimod A Cladribine

Week 1: Patients receive Cladribine 10mg scon three consecutive days.

Week 5: WBC will be obtained. Once results are available patients receive either NO further injections, OR - starting on the same day - up to three further injections: - If lymphocytes are >1 (x109): Cladribine 10mg sc will be given on three consecutive days. - If lymphocytes are 0.8-1 (x109): Cladribine 10mg sc will be given on two consecutive days. - If lymphocytes are 0.5-0.8 (x109): Cladribine 10mg sc will be given on one day. - If lymphocytes are below 0.5 (x109): NO further Cladribine will be given. B Laquinimod - Laquinimod given as a once daily dose of between 0.6mg and 1,5mg -On and after week 1, day 4 of cladribine administration except for those days where subsequent doses of cladribine are administered.

From week 1, day 1 of cladribine administration

Example 2: Assessment of cladribine and laquinimod combination therapy in the treatment of MS

Clinical trial design to demonstrate the proposed therapeutic effects. A clinical trial will include pwMS diagnosed according to the latest criteria, with a baseline Expanded Disability Status Scale (EDSS) between 0 and 5 and either at least one relapse within the last 12 months of randomisation and a previous MR I scanning showing lesions consistent with multiple sclerosis orGd enhanced lesions on MRI scan done within 6 months of randomisation. Excluded will be patients with a relapse within 50 days of randomisation or no stabilization from a previous relapse. Patients will also be excluded if they have been treated within the last four years prior to randomization with alemtuzumab, rituximab, ocrelizumab or haematopoetic stem cell transplantion. Patients who within the last year have been treated with T-cell or T-receptor vaccination, total lymphoid irradiation or therapeutic monoclonal antibody treatment, who had been treated with mitoxantrone or cyclophosphamide within the last year of randomisation will also be excluded As will patients who within 6 months of randomisation had been treated with cyclosporine, azathioprine, methotrexate or plasmapheresis. Patients with previous gastrointestinal disease such as ulcus duodeni, gastritis or pancreatic disease will be excluded as well. Patients with lymphocytopaenia, low white blood cell count or calculated creatinine clearance of < 60 mL/min at baseline will also be excluded. The trial will be approved by all relevant Competent Agencies as well as all relevant Ethic Committees. The trial will be a randomized, double-dummy, controlled parallel group design testing on or more active treatment arm(s) and either an active comparator(DMD currently licensed for multiple sclerosis) ora placebo arm.

Lymphocyte markers and monocyte counts are monitored in trial participants. Participants are monitored to determine whether there is any progression or improvement of brain lesions associated with progression of MS through MRI scans and neurological examination as described in Miller et al, 1996, above; Evans etal, 1997, above; Sipe et al., 1984, above; and Mattson, 2002, above. The patient's disability progression and the time for having a first relapse are monitored as well as the proportion of relapse-free patients at 24 months.

The efficacy of the treatment is measured by the frequency of relapses in RRMS and the monitoring of the lesions in the CNS as detected using methods such as MRI technique (Miller etal, 1996, Neurology, 47(Suppl 4): S217; Evans etal, 1997, Ann. Neurology, 41:125-132).

The observation of the reduction and/or suppression of MRI T1 gadolinium-enhanced lesions (thought to represent areas of active inflammation) gives a primary efficacy variable. Secondary efficacy variables include number of combined active lesions per subject defined as new T1 gadolinium-enhancing, or new T2 non-enhancing, or enlarging lesions, or both (without double-counting); number of active T2 lesions per subject; number of active T1 gadolinium-enhanced lesions per subject; proportion of subjects with no active T2 lesions; proportion of subjects with no active T1 gadolinium-enhanced lesions; change in T2 lesion volume; relapse rate; Expanded Disability Status Scale score and Scripps Neurologic Rating Scale (SNRS) score (Sipe etal, 1984, Neurology, 34, 1368-1372).

Claims

1. A method for treating multiple sclerosis in a subject in need thereof, said method comprising administering to said subject cladribine ora pharmaceutically acceptable salt or hydrate thereof and laquinimod or a pharmaceutically acceptable salt or hydrate thereof.

2. A method according to claim 1 wherein the amount of cladribine is between 1-50mg/day.

3. A method according to claim 1 wherein the amount of laquinimod is between 0.1 -40mg/day.

4. A method according to any one of claims 1 to 3 comprising administering cladribine to a subject according to the steps: (i) An induction period wherein cladribine is administered and wherein the total dose of cladribine reached at the end of the induction period is from about 0.5 mg/kg to about 5.0 mg/kg; (ii) A cladribine-free period wherein no cladribine is administered; (iii) A maintenance period wherein cladribine is administered and wherein the total dose of cladribine administered during the maintenance period is lower than or equal to the total dose of cladribine reached at the end of the induction period (i); (iv) A cladribine-free period wherein no cladribine is administered.

5. A method according to any one of claims 1 to 4 wherein the multiple sclerosis is relapsing multiple sclerosis.

6. A method according to any one of claims 1 to 5 wherein cladribine is administered orally, intravenously or subcutaneously.

7. A method according to any one of claims 1 to 5 wherein laquinimod is administered orally, intravenously or subcutaneously.

8. A method according to any one of claims 1 to 7 wherein cladribine and laquinimod are administered simultaneously.

9. A method according to any one of claims 1 to 7 wherein the administration of cladribine precedes the administration of laquinimod.

10. A method according to any one of claims 1 to 7 wherein the administration of laquinimod precedes the administration of cladribine.

11. A method according to any one of claims 1 to 10 wherein the administration of cladribine and laquinimod continues for more than 30 days.

12. A pharmaceutical composition comprising cladribine or a pharmaceutically acceptable salt or hydrate thereof, and laquinimod or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of multiple sclerosis.

13. A composition according to claim 12 which further comprises a pharmaceutically acceptable carrier.

14. A composition according to claim 12 or 13 wherein the laquinimod is laquinimod sodium.

15. A composition according to claim 12 or 13 wherein the cladribine is present in a therapeutically effective amount.

16. A composition according to claim 15 wherein the therapeutically effective amount is between 1-50mg.

17. A composition according to any one of claims 12 to 14 wherein the laquinimod is present in a therapeutically effective amount.

18. A composition according to claim 17 wherein the therapeutically effective amount is between 0.1 to40mg.

19. A kit comprising (a) a first pharmaceutical composition comprising an amount of cladribine and a pharmaceutically acceptable carrier; (b) a second pharmaceutical composition comprising an amount of laquinimod and a pharmaceutically acceptable carrier; and (c) instructions for use of the first and second pharmaceutical compositions together to treat multiple sclerosis in a subject in need thereof.

20. A kit according to claim 19 wherein the first and second pharmaceutical compositions are in the form of a tablet, powder or a liquid formulation.

21. A kit comprising a pharmaceutical composition comprising cladribine or a pharmaceutically acceptable salt or hydrate thereof, and laquinimod or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of multiple sclerosis.

22. A kit according to claim 21 wherein the pharmaceutical composition is in the form of a tablet, powder or a liquid formulation.