ES2495392T3 - Cladribine dosage regimen for the treatment of early progressive secondary multiple sclerosis - Google Patents

Abstract

The present invention is related to the use of Cladribine for the preparation of a pharmaceutical formulation for the treatment of multiple sclerosis, especially relapsing-remitting multiple sclerosis or early secondary progressive multiple sclerosis, wherein the preparation is to be the orally administered and wherein re-treatments are possible.

Description

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DESCRIPTION

Cladribine dosage regimen for the treatment of early progressive secondary multiple sclerosis

Area of the invention

The invention generally refers to the use of multiple doses of cladribine for the treatment of multiple sclerosis. The invention refers to the use of multiple doses of cladribine for the treatment of early progressive secondary multiple sclerosis. Additionally, the use of multiple doses of cladribine for the treatment of relapsing-remitting multiple sclerosis is also revealed.

Background of the invention

Multiple sclerosis (MS) is the best known chronic inflammatory demyelinating disease of the central nervous system in humans. The onset of the disease usually occurs during the age range of 20 to 40 years. Women are affected approximately twice as much as men.

Over time, MS leads to the accumulation of various neurological disabilities. It is assumed that clinical disability in MS is the result of repeated inflammatory injury with subsequent loss of myelin and axons, which leads to tissue atrophy.

MS manifests itself in physical symptoms (relapses and progression of disability), inflammation of the central nervous system (CNS), cerebral atrophy and cognitive disability. Symptoms that occur include focal sensory deficits, focal weakness, visual problems, lack of balance and fatigue. Sexual dysfunction and sphincter dysfunction may also occur. Approximately half of patients with MS may experience cognitive disability or depression.

Currently, MS is considered to be a multiphasic disease and periods of clinical latency (remissions) may occur between exacerbations. Remissions vary in duration and can last several years, but are rarely permanent. Four courses of the disease are individualized: multiple relapsing-remitting sclerosis (RR), progressive secondary (SP), progressive primary (PP), and progressive recurrent (RP).

More than 80% of patients with MS will initially show an RR course with clinical exacerbation of neurological symptoms, followed by a recovery that may or may not be complete (Lublin and Reingold, Neurology, 1996, 46: 907-911).

During the EMRR, an accumulation of disability occurs as a result of an incomplete recovery of relapses. Approximately half of the patients with RRMS change to a progressive course, called EMSP, 10 years after the onset of the disease. During the SP phase, a worsening of disability occurs as a result of the accumulation of residual symptoms after the exacerbation, but also of the insidious progression between the periods of exacerbation (Lublin and Reingold mentioned above). 10% of MS patients have PPMS that is characterized by the insidious progression of symptoms since the onset of the disease. Less than 5% of patients present with EMRP and are often considered to have the same prognosis as EMPP. It is suggested that different pathogenic mechanisms may be involved in different subgroups of patients and have very different implications for the classification of the disease (Lassmann et al., 2001, Trends Mol. Med., 7, 115-121; Lucchinetti et al. ., Curr. Opin. Neurol., 2001, 14, 259-269).

The onset of MS is defined by the presence of the first neurological symptoms of CNS dysfunction. Advances in cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) analyzes have simplified the diagnostic process and facilitated early diagnosis (Noseworthy et al., The New England Journal of Medicine, 2000, 343, 13, 938-952). The International Study Panel for the diagnosis of MS provided revised criteria that facilitate the diagnosis of MS and that includes MRI along with clinical and para-clinical diagnostic methods (Mc Donald et al., 2001, Ann. Neurol. , 50: 121-127).

Current medications for MS that are disease-modifying treatments, that is, that modify the course of MS, modulate or suppress the immune system. There are four FDA-approved immunomodulatory agents for RRMS: three beta interferons (Betaseron®, Berlex; Avonex®, Biogen; Rebif®, Serono) and glatiramer acetate (Copaxone®, Amgen). There is also an FDA-approved immunosuppressive drug for the worsening of MS, Mitoxantrone (Novantrone®), Amgen). Various different immunosuppressive agents are used, although they are not approved by the FDA.

Among them, it has been suggested that cladribine, a chlorinated purine analogue, 2-chloro-2'-deoxyadenosine analogue (2-CdA), is useful in the treatment of MS (EP 626853B1 and US 5,506,214) .

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Several clinical studies with cladribine in patients with multiple sclerosis have investigated the use of intravenous (i.v.) and subcutaneous (s.c.) cladribine in MS.

Two studies were conducted in Phase II double-blind, placebo-controlled respectively, in the treatment of chronic progressive MS (Selby et al., 1998, Can. J. Neurol. Sci., 25: 295-299) and remitting MS- recurrent, respectively (Romine et al., 1999, Proceedings of the Association of American Physicians, 111, 1, 35-44).

In the first trial, the dose of cladribine used was 0.1 mg / kg / day for 7 days by continuous intravenous infusion. The treatment was repeated for 4 consecutive months.

In the second clinical trial, the dose of cladribine used was 0.07 mg / kg / day for 5 days by subcutaneous injection. The treatment was repeated for 6 consecutive months.

In addition, a placebo-controlled Phase III study was conducted in patients with progressive primary multiple sclerosis (PP) or progressive secondary sclerosis (SP) (Rice et al., 2000, Neurology, 54, 5, 1145-1155). In this study, both groups of patients received cladribine by subcutaneous injection at a dose of 0.07 mg / kg / day. The treatment was repeated for 2 months or 6 months.

Phase II clinical studies provided evidence of the positive effects of cladribine in patients with MS in terms of assessments of the extended scale of Kurtzke disability status (EDSS), Scripps neurological evaluation scale (SNRS) and the conclusions of the magnetic resonance imaging (MRI) (Beutler et al., 1996, Proc. Nat. Acad. Sci. USA, 93, 1716-1720; Romine et al., 1999 mentioned above). The results of the Phase III studies were positive in terms of the significant reduction in brain lesions measured by MRI (Rice at al., 2000, mentioned above).

Some adverse effects (AD), such as an increased incidence of infections related to a compromised function of the immune system or with myelosuppression, were observed with the highest doses (Selby et al., 1998, mentioned above; Beutler et al., 1994 , Acta hematol., 91: 10-15). Due to the narrow safety margin between an effective dose and a dose with the appearance of AD, to date, all clinical trials for cladribine in multiple sclerosis have been carried out using its administration intravenously or subcutaneously. As a result, Beutler et al. (in Beutler et al., 1996, Seminars in Hematology, 33, 1 (S1), 4552) excluded the oral route for the treatment of multiple sclerosis with cladribine.

Grieb et al. reported on a small trial in 11 patients with relapsing-remitting multiple sclerosis (in Grieb et al., 1995, Archivum Immunologiae et Therapiae Experimentalis, 43 (5-6), 323-327), where cladribine was administered orally during 6 months over the course of 5 days, at a total dose of approximately 4-5.7 mg / kg (patients of approximately 52 and 75 kilos, respectively), that is, a total effective dose of 2-2.85 mg / kg For some patients, a single 5-day retreat was performed at a cumulative dose of 0.4-0.66 mg / kg after a cladribine-free period of 3 or 6 months. It was determined that the side effects observed with the previous regimen were less severe than those observed in the study in patients suffering from chronic progressive multiple sclerosis treated by intravenous infusion of cladribine (Sipe et al., 1994, Lancet 344, 9-13 ), but they were still present. In addition, the therapeutic efficacy of the oral regimen versus intravenous infusion therapy was questioned (Grieb et al., 1995, mentioned above) and a “no response” group (to treatment) has been identified (Stelmasiak et al., 1998 , Laboratory Investigations, 4 (1), 4-8; Stelmasiak et al., 1998, Medical Science Monitor, 4 (1), 4-8).

Therefore, it would be desirable to have a treatment for multiple sclerosis that includes oral administration of cladribine that would allow a similar or improved effect on MS lesions, while reducing the occurrence and / or severity of reactions. Adverse In addition, because MS is a chronic disease, it would be desirable to reduce the occurrence and / or severity of adverse reactions, so that retreatments are possible. A sustained benefit of cladribine treatment between treatment periods is also desirable.

Summary of the Invention

The present invention is directed to the use of cladribine for the preparation of a pharmaceutical formulation for the treatment of secondary progressive multiple sclerosis, wherein the preparation is administered orally as defined in the claims. In particular, the invention is directed to the use of cladribine for the preparation of a medicament for the treatment of early progressive secondary multiple sclerosis and where retreatments are possible.

An embodiment described in the present patent provides an improved dosage regimen for cladribine in the treatment of early progressive secondary multiple sclerosis as defined in the claims.

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A further embodiment of the invention provides a use of cladribine for the preparation of a pharmaceutical formulation for the treatment of early progressive secondary multiple sclerosis where adverse effects are reduced, allowing greater use of cladribine such as It is defined in the claims.

In one embodiment, the invention provides a use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive secondary multiple sclerosis where the formulation is administered orally following the sequential steps shown below:

(i)

an induction period lasting from 2 months to 4 months, wherein said pharmaceutical formulation of cladribine is to be administered and where the total dose of cladribine reached at the end of the induction period is approximately 1.7 mg / kg to approximately 3.5 mg / kg;

(ii)

a cladribine-free period that lasts from 8 months to 10 months where no cladribine is administered;

(iii) a maintenance period that lasts from 2 months to 4 months where said cladribine pharmaceutical formulation is to be administered and where the total dose of said cladribine reached at the end of the maintenance period is less than the total cladribine dose reached at the end of the induction period (i);

(iv)

a cladribine-free period where no cladribine is administered.

In another embodiment, the invention provides a pharmaceutical formulation of cladribine for use in the treatment of progressive secondary multiple sclerosis, comprising oral administration of cladribine.

or of a formulation thereof in a patient in need thereof which follows the following sequential stages:

(i)

an induction period that lasts from 2 months to 4 months where the total dose of cladribine reached at the end of the induction period is approximately 1.7 mg / kg to approximately 3.5 mg / kg;

(ii)

a cladribine-free period that lasts from 8 months to 10 months where no cladribine is administered;

(iii) a maintenance period lasting from 2 months to 4 months in which said pharmaceutical formulation of cladribine is to be administered and where the total dose of cladribine reached at the end of the maintenance period is less than the total dose of cladribine reached at the end of the induction period (i);

(iv) a cladribine-free period where no cladribine is administered.

Detailed description of the invention

Definition

The "total dose" or "cumulative dose" refers to the total dose of cladribine administered during the treatment, ie the dose reached at the end of the treatment that is calculated by adding the daily doses. For example, the total dose of cladribine corresponding to a treatment of 0.7 mg / kg of cladribine per day for 5 days is 3.5 mg / kg or the total dose of cladribine corresponding to a treatment of 0.35 Cladribine mg / kg per day for 5 days is 1.7 mg / kg.

"The total effective dose" or "cumulative effective dose" refers to the bioavailable dose of cladribine after a given administration period, that is, the bioavailable dose reached at the end of the treatment that is calculated by adding the daily doses reduced by the bioavailability coefficient. For example, the total effective dose of cladribine corresponding to a treatment of 0.7 mg / kg of cladribine per day for 5 days, where the bioavailability of cladribine is approximately 40%, is 1.4 mg / kg, or the total effective dose of cladribine corresponding to a treatment of 0.35 mg / kg of cladribine per day for 5 days, where the bioavailability of cladribine is approximately 40%, is 0.7 mg / kg.

Typically, the bioavailability of cladribine or a cladribine formulation used in the context described herein is from about 30% to about 90%, preferably from about 40% to about 60%, such as for example approximately 50%

"One month" refers to a period of 28, 29, 30 or 31 days.

A "treatment" comprises the sequential sequence of an "induction treatment" and at least one "maintenance treatment". Usually, a treatment described herein comprises a "treatment of

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induction ”and about one, or about two or about three maintenance treatments. Usually, a treatment described in this document is 2 years (24 months) or 3 years (36 months) or 4 years (48 months).

An "induction treatment" consists of the sequential succession of (i) an induction period in which cladribine or the pharmaceutical preparation of cladribine as described herein is administered orally and (ii) a period free of cladribine An induction period lasts up to 4 months or up to 3 months or up to 2 months. For example, an induction period lasts from 2 to 4 months. An induction period consists of oral administration of cladribine or a pharmaceutical preparation thereof for 1 to 7 days each month.

A "cladribine-free period" is a period where no cladribine is administered to the patient. During a cladribine-free period, the patient can be left free of any type of administration, or the patient can be dosed with a placebo pill or other exception drug. A cladribine-free period lasts up to 10 months or up to 9 months or up to 8 months. For example, a period without cladribine lasts from 8 to 10 months, usually at least 8 months.

A "maintenance treatment" consists of the sequential succession of (i) a maintenance period, in which cladribine or the pharmaceutical preparation of cladribine, as described herein, is administered orally in a dose less than the dose of cladribine administered orally during induction treatment, and (ii) a period free of cladribine. A maintenance period lasts up to 4 months, or up to 3 months, or up to 2 months, preferably up to 2 months. For example, a maintenance period lasts from 2 to 4 months, preferably 2 months. A maintenance period consists of oral administration of cladribine or a pharmaceutical preparation thereof for 1 to 7 days each month.

Within the context described herein, the beneficial effect, including attenuation, reduction, decrease or decrease in pathological development after the onset of the disease, can be seen after one or more "treatments", after a "treatment induction ", after" maintenance treatment "or during a period free of cladribine.

A "daily dose" refers to the total dose of cladribine administered orally to the patient each day of administration. The daily dose can be achieved by a single or several administrations per day, such as, for example, once a day, twice a day or three times a day.

The dose administered to an individual, in the form of single or multiple doses, will vary depending on a variety of factors, including pharmacokinetic properties, conditions and characteristics of the patient (sex, age, body weight, health, size), extent of symptoms. , concurrent treatments, frequency of treatment and the desired effect.

Patients suffering from MS can be defined, for example, as those with clinically confirmed MS or confirmed by laboratory diagnosis according to the criteria of Schumacher or Poser (Schumacher et al., 1965, Ann. NY Acad. Sci. 1965 ; 122: 552-568; Poser et al., 1983, Ann. Neurol. 13 (3): 227-31).

"Relapses" involve neurological problems that occur over a short period, usually days but sometimes as small as hours or even minutes. These attacks most often involve motor, sensory, visual or coordination problems in the early stages of the disease. Later, bladder, intestinal, sexual and cognitive problems may occur. Sometimes the onset of the attack takes place over several weeks. The usual relapse of MS implies a period of worsening, with the development of neurological deficits, and then a stabilization phase, in which the patient does not show improvement but does not get worse, followed by a recovery period. Recovery usually begins within a period of a few weeks.

The "efficacy" of a treatment as described herein can be measured based on changes in the course of the disease, in response to a use according to the invention. For example, the efficacy of MS treatment can be measured by the frequency of relapses in the RRMS and the presence or absence of new lesions in the CNS, as detected using methods such as the MRI technique (Miller et al., 1996, Neurology, 47 (Suppl 4): S217; Evans et al., 1997, Ann. Neurology, 41: 125-132).

The observation of the reduction and / or suppression of gadolinium augmented lesions (believed to represent areas of active inflammation) by MRI in T1, provides a primary efficacy variable.

Secondary efficacy variables include increased brain injury volume by MRI in T1, number of lesions increased by MRI in T1, injury volume by MRI in T2 (believed to represent the total disease burden, i.e. demyelination, gliosis, inflammation and loss of axons), volume of hypointense lesion increased by MRI in T1 (believed to represent demyelination and loss of primary axons),

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time of evolution of MS, frequency and severity of exacerbations and time to exacerbation, assessment of the extended scale of disability status and assessment of the neurological evaluation scale of Scripps (SNRS) (Sipe et al., 1984, Neurology , 34, 1368-1372). Modes are described for the early and precise diagnosis of multiple sclerosis and for monitoring the evolution of the disease in Mattson, 2002, Expert Rev. Neurotherapeutics, 319-328.

The degree of disability of MS patients can be measured, for example, by assessing the extended scale of Kurtzke's disability status (EDSS) (Kurtzke, 1983, Neurology, 33, 1444-1452). Usually, a decrease in the assessment of the EDSS corresponds to an improvement in the disease and conversely, an increase in the assessment of the EDSS corresponds to a worsening of the disease.

Cladribine (2-CdA)

2-CdA and its pharmaceutically acceptable salts can be used in the practice of the present invention.

Cladribine can be formulated in any pharmaceutical preparation suitable for oral administration. Representative oral formulations of 2-CdA are described in the documents (WO 96/19230; WO 96/19229; US 6,194,395; US 5,506,214; WO 2004/087100; WO 2004/087101). Examples of ingredients for oral formulations are provided below.

The processes for the preparation of 2-CdA are well known in the art. For example, the preparation of 2-CdA is described in the documents (EP 173,059; WO 04/028462; WO 04/028462; US 5,208,327; WO 00/64918) and Robins et al., J. Am. Chem Soc., 1984, 106: 6379. Alternatively, pharmaceutical preparations of 2-CdA can be purchased through Bedford Laboratories, Bedford, Ohio.

The administration of cladribine orally may be in the form of a capsule, tablet, oral suspension or syrup. The tablet or capsules may contain from about 3 to 500 mg of cladribine. Preferably, they may contain from about 3 to about 10 mg of cladribine, more preferably about 3, about 5 or about 10 mg of cladribine. The capsules may be gelatin capsules and may contain, in addition to cladribine in the amount indicated above, a small amount, for example less than 5% by weight, of magnesium stearate or other excipient. The tablets may contain the above amount of the compound and a binder, which may be a solution of gelatin, a paste of starch in water, polyvinyl alcohol in water, etc., with a usual sugar coating.

Compositions

The compositions described herein may further comprise one or more additional pharmaceutically acceptable ingredients, such as alum, stabilizers, antimicrobial agents, buffers, coloring agents, flavoring agents and adjuvants.

The compositions described herein may be in the form of tablets or dragees formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients that include binders, fillers, lubricants, disintegrants and wetting agents. Binding agents include syrup, gum arabic, gelatin, sorbitol, tragacanth, starch mucilage and polyvinylpyrrolidone. Fillers include lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate and sorbitol. Lubricants include magnesium stearate, stearic acid, talc, polyethylene glycol and silica. Disintegrants include potato starch and sodium starch glycolate. Wetting agents include sodium lauryl sulfate. The tablets may be coated according to methods well known in the art.

The compositions described herein may also be liquid formulations that include:

aqueous or oleaginous suspensions, solutions, emulsions, syrups and elixirs. The compositions can also be formulated as a dry product to reconstitute with water or other suitable vehicle before use. Such liquid preparations may contain additives, including suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. Suspending agents include sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel and hydrogenated edible fats. Emulsifying agents include lecithin, sorbitan monooleate and gum arabic. Non-aqueous vehicles include edible oils, almond oil, fractionated coconut oil, oil esters, propylene glycol and ethyl alcohol. Preservatives include methyl or propyl p-hydroxybenzoate and sorbic acid.

Combination

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Cladribine can be administered alone or in combination with IFN-beta, prophylactically or therapeutically to an individual before, simultaneously or sequentially with other therapeutic regimens or agents (e.g., multiple drug regimens), in a therapeutically effective amount, especially therapeutic agents for the treatment of multiple sclerosis. The active agents that are administered simultaneously with other therapeutic agents, can be administered in the same or in different compositions and by the same or by different routes of administration.

In one embodiment, when cladribine is to be administered in combination with IFN-beta, IFN-beta is administered during the cladribine-free period.

In another embodiment, when cladribine is to be administered in combination with IFN-beta, IFN-beta is administered after "treatment" according to the invention.

The term "interferon-beta (IFN-β)", as used herein, is intended to include fibroblast interferon, in particular of human origin, as obtained by isolation of biological liquids or as obtained by techniques. of recombinant DNA, from prokaryotic or eukaryotic host cells, as well as their salts, functional derivatives, variants, analogs and active fragments.

Suitable IFN-β according to the present invention is commercially available, for example, as Rebif® (Serono), Avonex® (Biogen) or Betaferon® (Schering). The use of interferons of human origin according to the present invention is also preferred. The term interferon, as used herein, is intended to encompass salts, functional derivatives, variants, analogs and active fragments thereof.

Rebif® (recombinant human interferon-β) is the latest development in interferon therapy for multiple sclerosis (MS), and represents a significant advance in its treatment. Rebif® is interferon (IFN) -beta 1a, produced from mammalian cell lines. It was established that interferon beta-1a administered subcutaneously three times a week is effective in the treatment of relapsing-remitting multiple sclerosis (RRMS). Interferon beta-1a can have a positive effect on the long-term course of MS, reducing the number and severity of relapses and reducing the disease burden and disease activity measured by MRI.

The dosage of IFN-β in the treatment of relapsing-remitting MS according to the invention depends on the type of IFN-β used.

According to the present invention, when the IFN is recombinant IFN-β1b produced in E. coli, commercially available under the trademark Betaseron®, it can preferably be administered subcutaneously every two days at a dose of about 250 to 300 µg or 8 MUI to 9, 6 MUI per person.

According to the present invention, when the IFN is recombinant IFN-β1a, produced in Chinese hamster ovary cells (CHO cells), commercially available under the trademark Avonex®, it can preferably be administered intramuscularly once a week, in a dose of approximately 30 µg to 33 µg or 6 MUI to 6.6 MUI per person.

According to the present invention, when the IFN is recombinant IFN-β1a, produced in Chinese hamster ovary cells (CHO cells), commercially available under the trademark Rebif®, it can preferably be administered subcutaneously three times per week (TPS) at a dose of about 22 µg to 44 µg or 6 MUI to 12 MUI per person.

Patients

The patients described herein are patients suffering from multiple sclerosis, preferably from EMRR or early EMSP.

In an embodiment described herein, patients are selected from male or female humans between 18 and 55 years of age.

In another embodiment described herein, the patients presented at least one relapse within 12 months prior to treatment.

Use according to the invention

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In one embodiment, a use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive secondary multiple sclerosis is described herein, wherein the formulation is to be administered orally following the sequential steps a continuation:

(i)

an induction period lasting from 2 months to 4 months, wherein said pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the induction period is from about 1.7 mg / kg to about 3, 5 mg / kg;

(ii)

a cladribine-free period that lasts from 8 months to 10 months where no cladribine is administered;

(iii) a maintenance period that lasts from 2 months to 4 months, where the pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the maintenance period is less than the total dose of cladribine reached at end of induction period (i);

(iv) a cladribine-free period where no cladribine is administered.

In a further embodiment, a use is described herein where the induction period lasts from 2 months to 4 months or up to 3 months or 2 months.

In a further embodiment, a use is described herein where the induction period lasts 2 months.

In a further embodiment, a use is described herein where the induction period lasts from 2 months to 4 months.

In a further embodiment, a use is described herein where the total cladribine dose reached at the end of the induction period is approximately 1.7 mg / kg.

In a further embodiment, a use is described herein where the total cladribine dose reached at the end of the induction period is approximately 3.5 mg / kg.

In another additional embodiment, a use is described herein where the cladribine-free period lasts from 8 months to 10 months, or up to 9 months or 8 months.

In another additional embodiment, a use is described herein where the cladribine free period (ii) lasts 8 months.

In another additional embodiment, a use is described herein where the cladribine free period (ii) lasts at least 8 months, up to 10 months.

In another additional embodiment, a use is described herein in which the cladribine free period (ii) lasts from 8 months to 10 months.

In another additional embodiment, a use is described herein where the cladribine free period (iv) lasts up to 10 months.

In another additional embodiment, a use is described herein in which the period without cladribine (iv) lasts at least 8 months.

In another additional embodiment, a use is described herein where the periods free of cladribine (ii) and / or (iv) last between 8 and 10 months.

In another additional embodiment, a use is described herein where a placebo pill is administered during the cladribine-free period.

In yet another embodiment, a use is described herein where the cladribine-free period is free from any administration.

In another additional embodiment, this document describes a use in which the maintenance period lasts from 2 months to 4 months, or up to 3 months, or up to 2 months, preferably 2 months.

In another additional embodiment, a use is described herein where the total cladribine dose reached at the end of the maintenance period (iii) is approximately 1.7 mg / kg.

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In a further embodiment, a use is described herein where steps (iii) to (iv) are repeated at least once or twice.

In a preferred embodiment, a use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive secondary multiple sclerosis is described herein where the formulation is administered orally following the sequential steps detailed in continuation:

(i)

an induction period where said pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the induction period is about 1.7 mg / kg to about 3.5 mg / kg;

(ii)

a cladribine-free period where no cladribine is administered;

(iii) a maintenance period in which the pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the maintenance period is less than the total dose of cladribine reached at the end of the induction period (i);

(iv) a cladribine-free period in which no cladribine is administered;

wherein the induction period lasts from 2 months up to 4 months, or up to 3 months, or up to 2 months; the cladribine-free period (ii) lasts from 8 months to 10 months, or up to 9 months or 8 months; the maintenance period (iii) lasts 2 months; the cladribine-free period (iv) lasts 10 months, and stages (iii) to (iv) will be performed repeatedly once, twice or three times.

This paper describes a use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive secondary multiple sclerosis, where the formulation is administered orally following the sequential steps that follow:

(i)

an induction period where the pharmaceutical formulation of cladribine is to be administered and where the total effective dose of cladribine reached at the end of the induction period is about 0.7 mg / kg to about 1.4 mg / kg;

(ii)

a cladribine-free period where no cladribine is to be administered;

(iii) a maintenance period where the pharmaceutical formulation of cladribine is administered and where the total effective dose of cladribine reached at the end of the maintenance period (iii) is lower than the total effective dose of cladribine reached at the end of the period of induction (i);

(iv)

a cladribine-free period where no cladribine is to be administered.

This paper describes a use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive secondary multiple sclerosis, where the formulation is administered orally following the sequential steps that follow:

(i)

an induction period wherein said pharmaceutical formulation of cladribine is administered and where the total effective dose of cladribine reached at the end of the induction period is from about 0.7 mg / kg to about 1.4 mg / kg;

(ii)

a cladribine-free period where no cladribine is administered;

(iii) a maintenance period where said cladribine pharmaceutical formulation is administered and where the total effective cladribine dose reached at the end of the maintenance period is less than the total effective cladribine dose reached at the end of the induction period (i );

(iv)

a cladribine-free period where no cladribine is administered; wherein the induction period lasts up to 4 months, or up to 3 months, or up to 2 months; the cladribine-free period (ii) lasts up to 10 months, or up to 9 months, or up to 8 months; the maintenance period (iii) lasts up to 2 months; the cladribine free period

(ii)

lasts up to 10 months; The total effective cladribine dose reached at the end of the maintenance period is approximately 0.7 mg / kg and stages (iii) to (iv) will be performed repeatedly once, twice or three times.

In a preferred embodiment, cladribine is described herein for use as a medicament for the treatment of progressive secondary multiple sclerosis where the medicament is administered orally following the sequential steps below:

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(i)

an induction period where the pharmaceutical formulation of cladribine is to be administered and where the total dose of cladribine reached at the end of the induction period is about 1.7 mg / kg to about 3.5 mg / kg;

(ii)

a cladribine-free period where no cladribine is administered;

(iii) a maintenance period where the pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the maintenance period is approximately 1.7 mg / kg;

(iv) a cladribine-free period in which no cladribine is administered;

wherein the induction period lasts from 2 months to 4 months, or up to 3 months, or up to 2 months; the cladribine-free period (ii) lasts up to 10 months, or up to 9 months, or up to 8 months; the maintenance period (iii) lasts up to 2 months; the cladribine-free period (iv) lasts up to 10 months, and stages (iii) to (iv) will be performed repeatedly once, twice or three times.

In another embodiment, a use of cladribine is described herein wherein the pharmaceutical formulation is administered orally at a daily dose of about 3 to 30 mg of cladribine, preferably 5 to 20 mg of cladribine, more preferably 10 mg cladribine

In another additional embodiment, a use is described herein where the total dose of cladribine reached at the end of the induction period is approximately 3.5 mg / kg, and the total dose of cladribine reached at the end of the period of Maintenance is approximately 1.7 mg / kg.

In another additional embodiment, a use is described herein where the total effective dose of cladribine reached at the end of the induction period is approximately 1.4 mg / kg and the total effective dose of cladribine reached at the end of the Maintenance period is approximately 0.7 mg / kg.

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally once a day during the induction period.

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally several times a day, is administered once a day during the induction period, preferably two or three times a day, more preferably twice a day.

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally 1 to 7 days a month, preferably 5 to 7 days a month during the induction period.

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally from about 0.02 days / kg to about 0.08 days / kg per month during the induction period.

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally from about 0.02 days / kg to about 0.08 days / kg per month during the maintenance period.

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally at a daily dose of approximately 10 mg of cladribine from day 1 to day 2, every month during the induction period. .

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally at a daily dose of approximately 10 mg of cladribine from day 1 to day 3, every month during the induction period. .

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally at a daily dose of about 10 mg of cladribine from day 1 to about day 4, every month during the period of induction.

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally at a daily dose of approximately 10 mg of cladribine from day 1 to day 5, every month during the induction period. .

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In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally at a daily dose of approximately 10 mg of cladribine from day 1 to day 6, every month during the induction period. .

In another embodiment, a use is described herein where the pharmaceutical formulation is administered orally at a daily dose of approximately 10 mg of cladribine from day 1 to day 4 each month during the induction period, and wherein the pharmaceutical formulation is a pharmaceutical formulation described in WO 2004/087101 or in WO 2004/087100.

In another embodiment, a use is described herein where the pharmaceutical formulation is administered in combination with interferon-beta.

A pharmaceutical formulation of cladribine for use in the treatment of progressive secondary multiple sclerosis is described herein, wherein the formulation is administered orally following the sequential steps below:

(i)

an induction period where said pharmaceutical formulation of cladribine is administered, and where the total dose of cladribine reached at the end of the induction period is from about 1.5 mg / kg to about 3.5 mg / kg;

(ii)

a cladribine-free period where no cladribine is administered;

(iii) a maintenance period in which the pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the maintenance period is less than the total dose of cladribine reached at the end of the induction period (i);

(iv)

a cladribine-free period where no cladribine is administered.

A pharmaceutical cladribine formulation for use in the treatment of progressive secondary multiple sclerosis is described herein, where the formulation is administered orally following the sequential steps below:

(i)

an induction period where said pharmaceutical formulation of cladribine is administered, and where the total effective dose of cladribine reached at the end of the induction period is from about 0.7 mg / kg to about 1.4 mg / kg;

(ii)

a cladribine-free period where no cladribine is administered;

(iii) a maintenance period where said pharmaceutical formulation of cladribine is administered, and where the total effective dose of cladribine reached at the end of the maintenance period is less than the total effective dose of cladribine reached at the end of the induction period ( i);

(iv) a cladribine-free period where no cladribine is administered.

In another embodiment, a pharmaceutical formulation of cladribine is described herein where steps (iii) to (iv) are to be repeated at least once or twice.

A pharmaceutical formulation of cladribine for use in the treatment of progressive secondary multiple sclerosis is described herein, wherein the formulation is administered orally following the sequential steps below:

(i)

an induction period in which said pharmaceutical formulation of cladribine is administered, and where the total dose of cladribine reached at the end of the induction period is from about 1.7 mg / kg to about 3.5 mg / kg;

(ii)

a cladribine-free period where no cladribine is administered;

(iii) a maintenance period, wherein said pharmaceutical formulation of cladribine is administered, and where the total dose of cladribine reached at the end of the maintenance period is less than the total dose of cladribine reached at the end of the induction period (i );

(iv) and optionally, a cladribine-free period where no cladribine is administered.

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A pharmaceutical formulation of cladribine for use is described herein, wherein the induction period lasts up to 4 months, or up to 3 months, or up to 2 months.

In another embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein the total dose of cladribine reached at the end of the induction period is approximately 1.7 mg / kg.

In another embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein the total dose of cladribine reached at the end of the induction period is approximately 3.5 mg / kg.

In another embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein the total effective dose of cladribine reached at the end of the induction period is approximately 1.4 mg / kg.

In another embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein the cladribine-free period lasts up to 10 months, or up to 9 months, or up to 8 months.

In another embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein the maintenance period lasts up to 4 months, or up to 3 months or up to 2 months.

In an even more preferred embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein the total dose of cladribine reached at the end of the maintenance period is approximately 1.7 mg / kg.

A pharmaceutical formulation of cladribine for use is described herein, wherein the total effective dose of cladribine reached at the end of the maintenance period is approximately 0.7 mg / kg.

In an even more preferred embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein the maintenance period is followed by a period free of cladribine.

In a further embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein the total dose of cladribine reached at the end of the induction period is approximately 3.5 mg / kg and the total dose of Cladribine reached at the end of the maintenance period is approximately 1.7 mg / kg.

A pharmaceutical formulation of cladribine for use is described herein, wherein the total effective dose of cladribine reached at the end of the induction period is approximately 1.4 mg / kg and the total effective dose of cladribine reached at the end of the Maintenance period is approximately 0.7 mg / kg.

In a further embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein cladribine is administered orally at a daily dose of about 3 to about 30 mg.

In a further embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein cladribine is administered orally at a daily dose of approximately 10 mg.

In a further embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein cladribine is administered orally 1 to 7 days per month during the induction period.

In a further embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein steps (iii) to (iv) are repeated at least once or twice.

In a further embodiment, a pharmaceutical formulation of cladribine for use is described herein, wherein cladribine is administered in combination with interferon-beta.

Examples

The following abbreviations refer respectively to the following definitions: kg (kilogram), µg (microgram), mg (milligram), EA (adverse effects), CNS (central nervous system), CSF (cerebrospinal fluid), EDSS ( expanded disability status scale), SNRS (neurological assessment scale of

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Scripps), IFN (interferon), i.v. (intravenous), MUI (millions of international units), MS (multiple sclerosis), MRI (magnetic resonance imaging), v.o. (oral route), PPMS (progressive primary multiple sclerosis), RRMS (progressive recurrent multiple sclerosis), RRMS (relapsing-remitting multiple sclerosis), SPMS (progressive secondary multiple sclerosis), s.c. (subcutaneous), TPS (three times per week), 2-CdA (2-chloro-2'deoxyadenosine

5 or cladribine), UI (international units).

The efficacy and safety of oral administration of cladribine, finally administration of multiple doses, according to the invention can be evaluated, for example, by following the protocol below:

Example 1: Oral cladribine in the treatment of recurrent forms of MS

A study of sixty patients with recurrent forms of clinically confirmed multiple sclerosis is performed.

10 Each patient is examined first for normal liver, kidney and bone marrow functioning to establish baseline values.

Patients are selected from among men or women, between 18 and 55 years of age who presented one or more relapses in the previous 12 months. Female patients are non-pregnant women.

Patients are randomly assigned to one of the treatment groups listed in Table 1 below:

15 Table 1

Groups

2-CdA

one

-

2

1.75 mg / kg

3

3.5 mg / kg

Each patient in Groups 2 and 3 receives 3 mg or 10 mg of 2-CdA (1, 2 or 3 administrations per day depending on the patient's weight), combined in a cyclodextrin formulation as described in the document. WO 2004/087101, Example 3. Cladribine compositions in tablets of 3 mg or 10 mg of 2

20 CdA containing hydroxypropyl-beta-cyclodextrin are detailed in Table 2 below:

Table 2

Ingredients Name

Formula mg / tablet Formula mg / tablet

Cladribine-2-hydroxypropyl-Bcyclodextrin complex *

153.75 equivalent to 10 mg of 2-CdA 30.60 equivalent to 3 mg of 2-CdA

Sorbitol powder

44.25 68.4

Magnesium stearate (vegetable grade)

2.0 1.00

Total

200.0 100

* Cladribine is in complex and lyophilized with 2-hydroxypropyl-B-cyclodextrin as a separate process, as described in WO 2004/087101.

Examples of administration schedules for the induction period depending on the weight of the patient are given below in Tables 3 and 4 for the target doses of 1.75 mg / kg and 3.5 mg / kg, respectively. 25 For the maintenance period, the example administration scheme in Table 3 applies.

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Table 3

Patient weight ranges (kg)

Total target dose (kg) equivalent to 1.75 mg / kg Number of pills (10 mg) / induction period

Min

Middle range Max  Min Max Month 1 Month 2 Total

40

42.5 44.9 28 31.4 4 3 7

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47.5 49.9 31.5 34.9 4 4 8

fifty

52.5 54.9 35 38.4 5 4 9

55

57.5 59.9 38.5 41.9 5 5 10

60

62.5 64.9 42 45.4 5 5 10

65

67.5 69.9 45.5 48.9 6 5 eleven

70

72.5 74.9 49 52.4 6 6 12

75

77.5 79.9 52.5 55.9 7 6 13

80

82.5 84.9 56 59.4 7 6 13

85

87.5 89.9 59.5 62.9 7 7 14

90

92.5 94.9 63 66.4 8 7 fifteen

95

97.5 99.9 66.5 69.9 8 8 16

100

102.5 104.9 70 73.4 9 8 17

105

107.5 109.9 73.5 76.9 9 9 18

110

112.5 114.9 77 80.4 9 9 18

115

117.5 119.9 80.5 83.9 10 9 19

Table 4:

Patient weight ranges (kg)

Total target dose (kg) equivalent to 3.5 mg / kg Number of pills (10 mg) / induction period

Min

Middle range Max  Min Max Month 1 Month 2 Month 3 Month 4 Total

40

42.5 44.9 56 62.9 4 4 3 3 14

Four. Five

47.5 49.9 63 69.9 4 4 4 4 16

fifty

52.5 54.9 70 76.9 5 4 4 4 17

55

57.5 59.9 77 83.9 5 5 5 4 19

60

62.5 64.9 84 90.9 6 5 5 5 twenty-one

65

67.5 69.9 91 97.9 6 6 5 5 22

70

72.5 74.9 98 104.9 6 6 6 6 24

75

77.5 79.9 105 111.9 7 7 6 6 26

80

82.5 84.9 112 118.9 7 7 7 6 27

85

87.5 89.9 119 125.9 7 7 7 7 28

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Table 4 (continued)

Patient weight ranges (kg)

Total target dose (kg) equivalent to 1.75 mg / kg Number of pills (10 mg) / induction period

Min

Middle range Max  Min Max Month 1 Month 2 Month 3 Month 4 Total

90

92.5 94.9 126 132.9 8 8 7 7 30

95

97.5 99.9 133 139.9 8 8 8 8 32

100

102.5 104.9 140 146.9 9 8 8 8 33

105

107.5 109.9 147 153.9 9 9 9 8 35

110

112.5 114.9 154 160.9 10 9 9 9 37

115

117.5 119.9 161 167.9 10 10 9 9 38

In group 1 patients receive a placebo (saline solution) for 4 months followed by 8 months without treatment.

In group 2, patients receive a daily oral administration of cladribine for approximately 5 days a month for 2 months (induction period) of the 2-CdA formulation with cyclodextrin in such a way that the total effective dose administered at the end of first 2 months approximates approximately 0.7 mg / kg (total dose of approximately 1.75 mg / kg for a bioavailability of approximately 40%); followed by placebo administration for 2 months; followed for 8 months without treatment.

In group 3, patients receive a daily oral administration of cladribine for approximately 5 days a month for 4 months (induction period) of the 2-CdA formulation with cyclodextrin, such that the total effective dose administered at the end of first 4 months approximates approximately 1.4 mg / kg (total dose of approximately 3.5 mg / kg for a bioavailability of approximately 40%); followed by 8 months without treatment.

Starting at month 13, the 3 groups of patients received retreatment with cladribine formulation with cyclodextrin for approximately 5 days a month for 2 months (maintenance period) with the lowest dose (such that the total effective dose administered at the end of the first 2 months it approximates approximately 0.7 mg / kg) followed by 10 months without treatment.

Finally, starting at month 25, all groups of patients receive retreatment with cladribine formulation with cyclodextrin for approximately 5 days a month for 2 months (maintenance period) with the lowest dose (such that the total effective dose administered at the end of the first 2 months approximates approximately 0.7 mg / kg) followed by 10 months without treatment.

Patients are monitored to determine if there is any progression or improvement of brain lesions associated with the progression of MS by MRI scanners and neurological examinations, as described in Miller et al., 1996, mentioned above; Evans et al., 1997, mentioned above; Sipe et al., 1984, mentioned above; and Mattson, 2002, mentioned above. All patients have a baseline study and an MRI study (brain or spinal cord, depending on the location of the lesions) in the month

12.

The evolution of the patient's disability and the time to have a first relapse are monitored, as well as the proportion of patients without relapse at 24 months.

Lymphocyte markers and monocyte counts are monitored in patients.

Patients in Groups 2 and 3 have a decrease in brain lesions.

The data show that the 2-CdA dosage regimen consisting of the succession of an induction treatment and maintenance treatments is effective in reducing brain lesions, and no serious adverse effects are observed.

In addition, the invention refers to the following points:

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1. Use of cladribine for the preparation of a pharmaceutical formulation for the treatment of multiple sclerosis, where the formulation is administered orally following the sequential steps below:

(i)

an induction period where the pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the induction period is about 1.7 mg / kg to about 3.5 mg / kg;

(ii)

a cladribine-free period where no cladribine is administered;

(iii) a maintenance period in which the pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the maintenance period is less than the total dose of cladribine reached at the end of the induction period (i);

(iv) a cladribine-free period in which no cladribine is administered.

2.

Use according to point 1 where the induction period lasts up to 4 months, or up to 3 months, or up to 2 months.

3.

Use according to points 1 or 2 where the induction period lasts up to 2 months.

Four.

Use according to any of the preceding points where the induction period lasts up to 4 months.

5.

Use according to any of the preceding points where the total dose of cladribine reached at the end of the induction period is 1.7 mg / kg.

6.

Use according to any of the preceding points where the total dose of cladribine reached at the end of the induction period is 3.5 mg / kg.

7.

Use according to any of the preceding points where the cladribine free period lasts up to 10 months, or up to 9 months, or up to 8 months.

8.

Use according to any of the preceding points where the cladribine free period (iv) lasts up to 10 months.

9.

Use according to any of the preceding points where the maintenance period lasts up to 4 months, or up to 3 months or up to 2 months.

10.

Use according to any of the preceding points where the total dose of cladribine reached at the end of the maintenance period is 1.7mg / kg.

eleven.

Use according to point 1 where the formulation is administered orally following the sequential steps below:

(i)

an induction period where the pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the induction period is about 1.7 mg / kg to about 3.5 mg / kg;

(ii)

a cladribine-free period where no cladribine is administered;

(iii) a maintenance period in which the pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the maintenance period is less than the total dose of cladribine reached at the end of the induction period (i);

(iv) a free cladribine period where no cladribine is administered;

Where the induction period lasts up to 4 months, or up to 3 months or up to 2 months; the cladribine-free period (ii) lasts up to 10 months, or up to 8 months or up to 10 months; the maintenance period (iii) lasts up to 2 months; the cladribine free period (iv) lasts up to 10 months; The total cladribine dose reached at the end of the maintenance period is 1.7 mg / kg and steps (iii) to (iv) are repeated once, twice or three times.

12. Use according to any of the preceding points where the total dose of cladribine reached at the end of the induction period is 3.5 mg / kg and the total dose of cladribine reached at the end of the maintenance period is 1.7 mg. / kg

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13.

Use according to any of the preceding points where the pharmaceutical formulation is administered orally in a daily dose of 3 to 30 mg of cladribine.

14.

Use according to any of the preceding points where the pharmaceutical formulation is administered orally at a daily dose of 10 mg of cladribine.

5 15. Use according to any of the preceding points where the pharmaceutical formulation is administered orally from 1 to 7 days per month during the induction period.

16. Use according to any of the preceding points where steps (iii) to (iv) are repeated at least once or twice.

17. Use according to any of the preceding points where the pharmaceutical formulation is administered in combination with interferon-beta.

Claims (16)

5 10 fifteen twenty 25 30 35 40 E10182676 08-22-2014 1. Pharmaceutical formulation of cladribine for use in the treatment of early progressive secondary multiple sclerosis, where the formulation is administered orally following the sequential steps below:

(i)

an induction period lasting from 2 months to 4 months, wherein said pharmaceutical formulation of cladribine is to be administered and where the total dose of cladribine reached at the end of the induction period is approximately 1.7 mg / kg to approximately 3.5 mg / kg;

(ii)

a cladribine-free period that lasts from 8 months to 10 months, where no cladribine is administered;

(iii)

a maintenance period that lasts from 2 months to 4 months, where said cladribine pharmaceutical formulation is to be administered and where the total cladribine dose reached at the end of the maintenance period

(iii)

is lower than the total cladribine dose reached at the end of the induction period (i);

(iv) a cladribine-free period where no cladribine is administered. 2. Use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive secondary multiple sclerosis, where the formulation is administered orally following the sequential steps below:

(i)

an induction period lasting from 2 months to 4 months, wherein said pharmaceutical formulation of cladribine is to be administered and where the total dose of cladribine reached at the end of the induction period is about 1.7 mg / kg to about 3 , 5 mg / kg;

(ii)

a cladribine-free period that lasts from 8 months to 10 months, where no cladribine is administered;

(iii)

a maintenance period that lasts from 2 months to 4 months, where said cladribine pharmaceutical formulation is to be administered and where the total cladribine dose reached at the end of the maintenance period

(iii)

is lower than the total cladribine dose reached at the end of the induction period (i);

(iv) a cladribine-free period where no cladribine is administered. 3. Pharmaceutical formulation of cladribine for use in the treatment of progressive secondary multiple sclerosis, where the formulation is administered following the sequential steps below:

(i)

an induction period lasting from 2 months to 4 months, wherein said pharmaceutical formulation of cladribine is to be administered and where the total dose of cladribine reached at the end of the induction period is approximately 1.7 mg / kg to approximately 3.5 mg / kg;

(ii)

a cladribine-free period that lasts from 8 months to 10 months, where no cladribine is administered;

(iii)

a maintenance period that lasts from 2 months to 4 months, where said cladribine pharmaceutical formulation is to be administered and where the total cladribine dose reached at the end of the maintenance period

(iii)

it is about 1.7 mg / kg;

(iv) a cladribine-free period where no cladribine is administered. 4. Use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive secondary multiple sclerosis, where the formulation is administered orally following the sequential steps below:

(i)

an induction period lasting from 2 months to 4 months, wherein said pharmaceutical formulation of cladribine is to be administered and where the total dose of cladribine reached at the end of the induction period is approximately 1.7 mg / kg to approximately 3.5 mg / kg;

(ii)

a cladribine-free period that lasts approximately 8 months to 10 months, where no cladribine is administered;

(iii)

a maintenance period that lasts from 2 months to 4 months, where said cladribine pharmaceutical formulation is to be administered and where the total cladribine dose reached at the end of the maintenance period

(iii)

of approximately 1.7 mg / kg;

18 5 10 fifteen twenty 25 30 35 E10182676 08-22-2014 (iv) a cladribine-free period where no cladribine is administered.

5.

Pharmaceutical formulation of cladribine for use according to claim 1 or claim 3, or use according to claim 2 or claim 4, wherein the induction period lasts up to 4 months, or up to 2 months.

6.

Pharmaceutical formulation of cladribine for use or use according to any of the preceding claims, wherein the total dose at the end of the induction period is approximately 3.5 mg / kg.

7.

Pharmaceutical formulation of cladribine for use according to claim 1, claim 3 or claim 5 or the use according to claim 2, claim 4 or claim 5, wherein the total dose at the end of the induction period is approximately 1.7 mg / kg

8.

Pharmaceutical formulation of cladribine for use or use according to any of the preceding claims, wherein the cladribine-free period lasts up to 10 months.

9.

Pharmaceutical formulation of cladribine for use or use according to any of the preceding claims, wherein the maintenance period lasts up to 2 months.

10.

Pharmaceutical formulation of cladribine according to claim 3 for use or use according to claim 4, wherein the formulation is administered orally following the sequential steps below:

(i)

an induction period where said pharmaceutical formulation of cladribine is administered and where the total dose of cladribine reached at the end of the induction period is about 1.7 mg / kg to about 3.5 mg / kg;

(ii)

a cladribine-free period where no cladribine is administered;

(iii) a maintenance period where said pharmaceutical formulation of cladribine is administered; (iv) a cladribine-free period in which no cladribine is administered; where the maintenance period (iii) lasts 2 months; the cladribine free period (iv) lasts 10 months; The total cladribine dose reached at the end of the maintenance period is approximately 1.7 mg / kg and the stages (iii) to (iv) they will be performed repeatedly once, twice or three times.

eleven.

Pharmaceutical formulation of cladribine for use or use according to any of the preceding claims, wherein the total dose of cladribine reached at the end of the induction period is approximately 3.5 mg / kg and the total dose of cladribine reached at the end of the Maintenance period is approximately 1.7 mg / kg.

12.

Cladribine formulation for use or use according to any of the preceding claims, wherein the pharmaceutical formulation is administered orally at a daily dose of 3 to 30 mg of cladribine.

13.

Cladribine formulation for use or use according to any of the preceding claims, wherein the pharmaceutical formulation is administered orally at a daily dose of 10 mg of cladribine.

14.

Cladribine formulation for use or use according to any of the preceding claims, wherein the pharmaceutical formulation is administered orally from 1 to 7 days per month during the induction period.

fifteen.

Cladribine formulation for use or use according to any of the preceding claims, wherein steps (iii) to (iv) are repeated at least once or twice.

16.

Cladribine formulation for use or use according to any of the preceding claims, wherein the pharmaceutical formulation is administered in combination with interferon-beta.

19