Clartrobine therapy for treatment of progressive forms of multiple sclerosis

Abstract

The present invention relates to a clavabine therapy for the treatment of progressive forms of multiple sclerosis. In particular, the present invention relates to the use of specific oral doses, specific oral dosage forms and / or specific oral administration methods comprising clathrabine for the treatment of progressive forms of multiple sclerosis, in particular primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis, as well as methods of treatment based thereon.

Description

This application is a divisional application of an invention patent application filed on November 23, 2018, with application number 201880075672.5 and titled “Cladribine therapy for treating progressive forms of multiple sclerosis”. Technical Field

[0001] The present invention relates to the use of a specific oral dosage, a specific oral dosage form and / or a specific oral administration method comprising Cladribine for treating progressive forms of multiple sclerosis, in particular primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis. Background Art

[0002] Multiple sclerosis (MS) is a well-known chronic inflammatory demyelinating disease of the human central nervous system. The onset of the disease usually occurs between the ages of 20 and 40. Women are affected approximately twice as often as men.

[0003] Over time, MS can cause various neurological disabilities to accumulate. Clinical disability in MS is presumed to be the result of repeated inflammatory insults and subsequent loss of myelin and axons, causing tissue atrophy.

[0004] MS usually manifests as physical symptoms (relapses and disability progression), central nervous system (CNS) inflammation, brain atrophy and cognitive impairment. Presenting symptoms include focal sensory deficits, focal weakness, visual problems, imbalance and fatigue. Sexual disorders and sphincter dysfunction may occur. About half of patients with MS may experience cognitive impairment or depression.

[0005] MS is generally considered a multi-stage disease, with periods of clinical quiescence (remissions) occurring between exacerbations. Remissions vary in length and may last for years, but are rarely permanent.

[0006] Four disease courses are commonly distinguished: relapsing-remitting (RR) MS, secondary progressive (SP) MS, primary progressive (PP) MS, and progressive relapsing (PR) MS.

[0007] More than 80% of patients with MS will initially display a RR course with clinical exacerbations of neurological symptoms, followed by recovery that may or may not be complete (Lublin and Reingold, Neurology, 1996, 46:907-911).

[0008] During RRMS, disability accumulates due to incomplete recovery from relapses. About half of patients with RRMS switch to a progressive course, called SPMS, 10 years after disease onset. During the SP stage, worsening disability is caused not only by the accumulation of residual symptoms after exacerbations, but also by latent progression between exacerbations (Lublin and Reingold, above). 10% of MS patients suffer from PPMS, which is characterized by latent progression of symptoms from disease onset. Less than 5% of patients suffer from PRMS and are generally considered to have the same prognosis as PPMS. It has been suggested that different pathogenic mechanisms may involve different patient subgroups and have broad implications for disease classification (Lassmann et al., 2001, Trends Mol. Med., 7, 115-121; Lucchinetti et al., Curr. Opin. Neurol., 2001, 14, 259-269).

[0009] MS attacks are defined by the occurrence of the first neurological symptoms of CNS dysfunction. Advances in cerebrospinal fluid (CSF) analysis and magnetic resonance imaging (MRI) 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 MS Diagnostic Group has issued revised criteria that facilitate MS diagnosis and include MRI as well as clinical and quasi-clinical diagnostic methods (Mc Donald et al., 2001, Ann. Neurol., 50: 121-127).

[0010] Current drug treatments for MS are disease-modifying treatments, which modify the course of MS and modulate or suppress the immune system. In the past, there have been several FDA-approved immunomodulators for RRMS, including the following: three interferons ( Berlex; Biogen; Serono and Glatimarer Acetate ( There is also an FDA-approved immunosuppressive drug for exacerbations of MS, Mitoxantrone ( Amgen). Several other immunosuppressants are also in use, although not FDA approved. However, at the same time, the library of so-called disease modifying drugs (DMD) or disease modifying therapeutics / therapies (DMTs) includes the following: Interferon beta-1a, interferon beta-1a (e.g., ), Interferon beta-1b, interferon beta-1b (e.g., ), Pegylated interferon beta 1a (e.g. ), Alemtuzumab (eg, ), Daclizumab (e.g., ), Dimethyl fumarate (e.g. ), Fingolimod (eg, ), Glatiramer acetate (eg, ), Natalizumab (eg, ),and Teriflunomide (e.g., ).

[0011] The latest addition to this class of therapeutic agents is cladribine tablets Approved by the EMA in August 2017 for the treatment of relapsing-remitting multiple sclerosis in patients with high disease activity.

[0012] However, all of those therapeutic agents are only approved by health regulatory authorities (such as FDA, EMA) for the treatment of relapsing-remitting multiple sclerosis (RRMS), however, none of them are approved for progressive forms of multiple sclerosis, including (but not limited to) primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS).

[0013] In fact, there is only one approved therapeutic agent to date for the treatment of PPMS: Ocrelizumab. But to date, it has received at most moderate attention and success in this indication. Other clinical studies of PPMS, such as the PROMISE study (with glatiramer acetate as study drug), the OLYMPUS study (with rituximab as study drug), and the INFORMS study (with fingolimod as study drug), have not reached meaningful clinical endpoints. However, minimal clinical activity was seen in a subset of patients identified as early secondary progressive multiple sclerosis patients.

[0014] Interestingly, this so-called Early Secondary Progressive Multiple Sclerosis (ESPMS) is a form of multiple sclerosis that marks a transitional state between the relapsing-remitting form of MS and the progressive form of MS. This form combines very different aspects and very different mechanisms of both the pure relapsing-remitting form of MS and the progressive form of MS.

[0015] Thus, without wishing to be bound by theory, it is believed that the minimal efficacy or minimal clinical effect seen in all of the above-mentioned PPMS trials using DMDs other than ocelizumab (i.e., the DMDs originally approved for RRMS) is based on only a simple mechanism: all of the patients experiencing said minimal or modest efficacy of the DMDs approved for RRMS are actually patients in a transitional state between the relapsing-remitting form of MS and the progressive form of MS, which transitional state includes ESPMS, in which the RRMS aspects and mechanisms are treated exclusively (partially) without any effect or efficacy on the progressive aspects and mechanisms of SPMS or PPMS and their contribution to the patient's overall state. Thus, the extremely unsatisfactory results of the trials using the DMDs approved for RRMS discussed above clearly indicate that the mechanisms that are responsible for the relapsing-remitting form on the one hand and the progressive form on the other hand are extremely different and that those DMDs approved for RRMS are inaccessible.

[0016] Based on the foregoing, it is apparent that there is a high and unmet medical need for therapeutic agents that are effective in the area of ​​progressive forms of MS.

[0017] Based on the novel and unexpectedly favorable clinical results discussed in detail herein, without wishing to be bound by theory, it is believed that the specific oral doses, specific oral dosage forms, and / or specific oral administration regimens described herein comprising the active ingredient cladribine (recently approved for the treatment of RRMS in patients with high disease activity) are also effective in treating progressive forms of MS, significantly beyond ESPMS treatment, and are particularly effective in treating PPMS and / or SPMS, both when using cladribine as a single agent and in combination with other DMDs.

[0018] In more detail, results from the ONWARD study, which included both RRMS and SPMS patients, unexpectedly demonstrated that RRMS patients treated with cladribine (i.e., patients receiving oral cladribine in accordance with the now approved RRMS labeling for cladribine) were 50% less likely to have a qualified relapse than those treated with placebo, while SPMS patients treated with cladribine (i.e., SPMS patients also receiving oral cladribine in accordance with the now approved RRMS labeling for cladribine) were 89% less likely to have a qualified relapse than those treated with placebo. This significant difference in efficacy as demonstrated by the clinical data of the present application is a heretofore unexpected advantage for SPMS patients treated with cladribine, and clearly demonstrates the clinical efficacy and potential of cladribine in the treatment of progressive forms of MS, including both SPMS and PPMS, which appears to be significantly independent of co-medication administered to all patients, including those receiving placebo instead of cladribine. Remarkably, oral cladribine appears to be able to potently downregulate the targets and mechanisms of severely different inflammatory processes that are characteristic of progressive forms of MS, including preferably both SPMS and PPMS. Due to the unique properties of oral cladribine, including but not limited to a short half-life combined with prolonged pharmacodynamics (PD) and unique specific effects on various specific immune cells (most notably a reversible reduction in T-cell and B-cell counts with previously unknown selectivity), oral cladribine used in accordance with the present invention is believed to be a breakthrough therapeutic for the treatment of one or more progressive forms of MS, including but not limited to PPMS and / or SPMS (preferably PPMS).

[0019] Cladribine, a chlorinated purine analog 2-chloro-2'deoxyadenosine analog (2-CdA), has been shown to be useful in the treatment of MS (EP 626853B1 and US 5,506,214).

[0020] Use of Cladribine in Patients with Multiple Sclerosis Several clinical studies have investigated the use of intravenous and subcutaneous cladribine in MS.

[0021] Two double-blind, placebo-controlled Phase II studies were conducted in the treatment of the chronic progressive form of MS (Selby et al., 1998, Can. J. Neurol. Sci., 25:295-299) and relapsing-remitting MS (Romine et al., 1999, Proceedings of the Association of American Physicians, 111, 1, 35-44), respectively.

[0022] In the first trial, the dose of cladribine used was 0.1 mg / kg / day, given by continuous intravenous infusion for 7 days. Treatment was repeated for 4 consecutive months.

[0023] In the second clinical trial, the dose of cladribine used was 0.07 mg / kg / day, injected subcutaneously for 5 days. Treatment was repeated for 6 consecutive months.

[0024] In addition, a placebo-controlled phase III study was conducted in patients with primary progressive (PP) or secondary progressive (SP) multiple sclerosis (Rice et al., 2000, Neurology, 54, 5, 1145-1155). In this study, both patient groups received cladribine by subcutaneous injection at a dose of 0.07 mg / kg / day. Treatment was repeated for 2 or 6 months.

[0025] Phase II clinical studies provide evidence for the positive effects of cladribine in patients with MS in terms of Kutzke Extended Disability Status Scale (EDSS), Scripps Neurologic Rating Scale (SNRS) scores and magnetic resonance imaging (MRI) (Beutler et al., 1996, Proc. Nat. Acad. Sci. USA, 93, 1716-1720; Romine et al., 1999, supra). Phase III study results are positive for a significant reduction in MRI-measured brain damage (Rice et al., 2000, supra).

[0026] Some side effects (AEs) were observed at the highest doses, such as an increased incidence of infections associated with impaired immune function or bone marrow suppression (Selby et al., 1998, supra; Beutler et al., 1994, Acta hematol., 91: 10-15). Due to the narrow safety margin between the effective dose and the dose at which AEs occur, all clinical trials of cladribine in multiple sclerosis to date have been conducted using intravenous or subcutaneous administration. Therefore, Beutler et al. (Beutler et al., 1996, Seminars in Hematology, 33, 1 (S1), 45-52) ruled out the use of cladribine for the oral route of treatment of multiple sclerosis.

[0027] Grieb et al. reported a small trial in 11 patients with remitting-relapsing multiple sclerosis (Grieb et al., 1995, Archivum Immunologiae et Therapiae Experimentalis, 43 (5-6), 323-327), in which cladribine had been administered orally during a 5-day course every 6 months at a total dose of about 4-5.7 mg / kg (the patients were about 52 and about 75 kg, respectively), i.e. a total effective dose of 2-2.85 mg / kg. For some patients, a single retreatment for 5 days was performed after a cladribine-free cycle of 3 or 6 months with a cumulative dose of 0.4-0.66 mg / kg. The side effects observed with the above therapy are said to be less severe than those observed in a study of patients with chronic progressive multiple sclerosis treated by intravenous infusion of cladribine (Sipe et al., 1994, Lancet, 344, 9-13), but still exist. Additionally, the therapeutic efficacy of such oral therapies relative to intravenous infusion therapy has been questioned (Grieb et al., 1995, supra), and a group of "non-responders" has been identified (Stelmasiak et al., 1998, Laboratory Investigations, 4(1), 4-8).

[0028] Giovannoni et al. (N Engl J Med 2010) reported a placebo-controlled phase III trial of oral cladribine for relapsing multiple sclerosis (ClinicalTrials.gov number, NCT00213135). According to the trial, cladribine provides immune modulation by selectively targeting lymphocyte subtypes. Giovannoni et al. described the results of a 96-week phase 3 trial of short-term oral tablet treatment in patients with relapsing remitting multiple sclerosis. In this trial, 1326 patients were randomly assigned to receive one of two cumulative doses of cladribine tablets (3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo in a ratio close to 1:1:1, given in two or four short courses in the first 48 weeks, followed by two short courses starting at weeks 48 and 52 (a total of 8 to 20 days per year). The primary endpoint was the relapse rate at 96 weeks. In patients who received cladribine tablets (3.5 mg or 5.25 mg / kg), there was a significantly lower annual relapse rate than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of progression to 3-month sustained disability (hazard ratio in the 3.5 mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio in the 5.25 mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and a significant reduction in brain lesion counts on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine group included lymphopenia (21.6% in the 3.5 mg group and 31.5% in the 5.25 mg group, compared to 1.8%) and herpes zoster (8 patients and 12 patients, respectively, compared to no patients). Thus, treatment with cladribine tablets significantly reduced the relapse rate, risk of disability progression, and MRI measures of disease activity at 96 weeks. However, it is stated that the benefits need to be weighed against the risks.

[0029] Therefore, there is a need to have a method for treating multiple sclerosis comprising oral administration of cladribine which would allow the same or improved effect on MS damage while also reducing the occurrence of adverse events, the severity of adverse events and / or the progression of the disease overall in patients suffering from progressive forms of MS (preferably selected from PPMS and / or SPMS). In addition, since MS is a chronic disease, it is desirable to reduce the occurrence and / or severity of adverse events to enable retreatment. Sustained benefit of cladribine treatment between and / or beyond treatment cycles is also desirable. Brief description of the invention The present invention relates in particular to a novel use of cladribine for the preparation of an oral pharmaceutical formulation for the treatment of progressive forms of multiple sclerosis, including but not limited to primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis, wherein the pharmaceutical formulation is to be orally administered according to a defined therapy. In addition, the present invention relates to a specific method of treating a patient suffering from a progressive form of multiple sclerosis, including but not limited to primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis, the method comprising orally administering cladribine according to a defined therapy.

[0030] Furthermore, the present invention provides an improved dosing regimen for the oral use of cladribine in the treatment of progressive forms of multiple sclerosis.

[0031] A further aspect of the invention relates to the use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive forms of multiple sclerosis, wherein efficacy is provided to the patient and / or wherein side effects are reduced, thereby preferably providing a new treatment option for patients suffering from progressive forms of multiple sclerosis.

[0032] Furthermore, the present invention preferably provides the use of cladribine for the preparation of a pharmaceutical formulation, wherein the formulation is to be administered orally as described herein.

[0033] The efficacy of cladribine in treating progressive forms of MS, including PPMS and / or SPMS, may preferably be demonstrated by improvements in one or more of the expanded disability status scale (EDSS), no evidence of disease activity (NEDA), no evidence of progression or active disease (NEPAD), and / or quality of life (QoL), preferably as known and described in the art, and / or as described herein. Additionally or alternatively, it may be preferred to also use MRI measures of lesions to track efficacy, preferably as known and described in the art, and / or as described herein. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 Shown is the ONWARD study design. Figure 2 Shown are qualified relapse rates (annualized, adjusted) in patients with SPMS treated with cladribine tablets 3.5 mg / kg + IFN-β or placebo + IFN-β in ONWARD (89% risk reduction for SPMS patients treated with cladribine compared with placebo). Figure 3 Shown are qualified relapse rates (annualized, adjusted) in patients with RRMS treated with cladribine tablets 3.5 mg / kg + IFN-β or placebo + IFN-β in ONWARD (50% risk reduction for RRMS patients treated with cladribine compared with placebo). Figure 4 Shown is a schematic diagram of the study design for the PPMS study. DETAILED DESCRIPTION OF THE INVENTION The present invention is described in more detail in the sections given below: 1. Cladribine for oral treatment of patients with progressive forms of multiple sclerosis, wherein the cladribine is to be orally administered to each patient at a determined dose calculated per patient, per unit of body weight and per treatment year, wherein the dose or the determined dose is selected from the range of 1.5 mg / kg to 4.0 mg / kg. Preferably, the dose calculated per patient, per patient's body weight and per treatment year refers to a "fixed dose". Therefore, preferred is cladribine for oral treatment of patients with progressive forms of multiple sclerosis, wherein the cladribine is to be orally administered to each patient at a fixed dose per patient, per unit of body weight and per treatment year, wherein the fixed dose is selected from the range of 1.5 mg / kg to 4.0 mg / kg. Typically, a treatment year lasts about 12 months.

[0034] 2. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described in section 1, wherein the fixed dose is selected from the range of 1.5 mg / kg to 2.0 mg / kg, preferably from the range of 1.5 mg / kg to 2.0 mg / kg per year. Particularly preferred is Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described in section 1, wherein the fixed dose is selected from the range of 1.5 mg / kg to 2.0 mg / kg, preferably from the range of 1.5 mg / kg to 2.0 mg / kg per year, for two consecutive years of treatment. Thus, the fixed dose is preferably selected from the range of 3.0 mg / kg to 4.0 mg / kg over two consecutive years (or to be administered over 2 consecutive years), wherein the fixed dose is selected from the range of 1.5 mg / kg to 2.0 mg / kg per year in each of the 2 years.

[0035] 3. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described in sections numbered 1 and / or 2, wherein the fixed dose per patient is preferably 1.75 mg / kg per treatment year for each patient with a maximum deviation of + / - 0.2 mg / kg. Particularly preferred is Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described in sections numbered 1 and / or 2, wherein the fixed dose per patient is preferably 1.75 mg / kg per treatment year for each patient with a maximum deviation of + / - 0.2 mg / kg for two consecutive treatment years. Thus, the fixed dose per patient is preferably 3.5 mg / kg for each patient, preferably over two consecutive years, with a maximum deviation of + / - 0.4 mg / kg.

[0036] 4. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described in sections 1, 2 and / or 3, wherein the progressive form of multiple sclerosis comprises, and in particular consists of, primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis.

[0037] 5. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described in sections 1, 2, 3 and / or 4, wherein the progressive form of multiple sclerosis is primary progressive multiple sclerosis. Preferably, Cladribine is used according to the invention in patients who have been diagnosed with primary progressive multiple sclerosis before starting treatment. More preferably, Cladribine is used as described herein and in particular as described above and / or below in patients who have been diagnosed with primary progressive multiple sclerosis before starting treatment.

[0038] 6. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described in sections 1, 2, 3 and / or 4, wherein the progressive form of multiple sclerosis is secondary progressive multiple sclerosis. Preferably, Cladribine is used according to the invention in patients who have been diagnosed with secondary progressive multiple sclerosis prior to starting treatment. Preferably, secondary progressive multiple sclerosis does not include early secondary progressive multiple sclerosis.

[0039] 7. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to one or more of the preceding sections, wherein said Cladribine is to be orally administered to a patient between the ages of 18 and 65 years, preferably including a patient aged 18 years and a patient aged 65 years.

[0040] 8. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to one or more of the preceding sections, wherein said Cladribine is to be orally administered to a patient between the ages of 18 and 51 years, preferably including patients between the ages of 18 and 51 years.

[0041] 9. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to one or more of the preceding sections, wherein said Cladribine is to be orally administered to a patient between the ages of 12 and 51 years, preferably including patients aged 12 and aged 51 years.

[0042] 10. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the aforementioned numbered sections, wherein said cladribine is to be orally administered to a patient of female sex and / or to a patient of male sex. Since female patients are more often affected by progressive forms of multiple sclerosis and / or are often more severely affected by it, a preferred aspect of the invention in this respect is the treatment of female patients.

[0043] 11. Cladribine for use as described herein, preferably as described in one or more of the above and / or following numbered sections, and more preferably according to one or more of the above numbered sections, wherein the patient has high disease activity (HDA) and / or has been diagnosed with high disease activity. Preferably, cladribine is used according to the present invention for patients who have been diagnosed with high disease activity before starting treatment. More preferably, cladribine is used as described herein, preferably as described in one or more of the above and / or following numbered sections, and more preferably according to one or more of the above numbered sections, for patients who have been diagnosed with high disease activity before starting treatment.

[0044] 12. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein said cladribine is to be orally administered to a patient who has not been treated with cladribine and / or a disease-modifying drug other than cladribine.

[0045] 13. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of sections 1 to 11, wherein said cladribine is to be orally administered to a patient who has previously received cladribine and / or a disease-modifying drug other than cladribine. Preferably, in this aspect, the disease-modifying drug other than cladribine comprises interferon beta-1a, beta interferon-1a (e.g., ).

[0046] 14. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein said cladribine is to be orally administered to a patient who is also receiving one or more disease modifying drugs other than cladribine. Preferably, in this aspect, disease modifying drugs other than cladribine include interferon beta-1a, beta interferon-1a (e.g., ).

[0047] 15. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of sections 12-14, wherein the disease modifying drug other than cladribine is selected from: Interferon beta-1a, interferon beta-1a (e.g., ), Interferon beta-1b, interferon beta-1b (e.g., ), Pegylated interferon beta 1a (e.g. ), Alemtuzumab (eg, ), Daclizumab (eg, ), Dimethyl fumarate (e.g. ), Fingolimod (eg, ), Glatiramer acetate (eg, ), Natalizumab (eg, ),and Teriflunomide (e.g., ).

[0048] 16. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the cladribine is to be orally administered to each patient at a fixed dose per patient, per unit of body weight and per treatment year, wherein the fixed dose is selected from the range of 1.5 mg / kg to 4.0 mg / kg, preferably from the range of 1.5 mg / kg to 2.0 mg / kg, and particularly preferably is 1.75 mg / kg per treatment year for each patient with a maximum deviation of + / - 0.2 mg / kg, and wherein the fixed dose is orally administered to the patient within two consecutive months within the treatment year, preferably within two consecutive months at the beginning of the treatment year.

[0049] 17. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to section 16, wherein the fixed dose is orally administered to the patient within two consecutive months starting at the beginning of the treatment year. More preferred is Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to section 16, wherein the fixed dose is orally administered to the patient within two consecutive months starting at the beginning of each of the treatment years.

[0050] 18. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to sections 16 and / or 17, wherein the fixed dose is orally administered to the patient within one or two weeks, preferably within two consecutive weeks, in each of the two consecutive months.

[0051] 19. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to sections 16, 17 and / or 18, wherein the fixed dose is orally administered to the patient in a week or two consecutive weeks at the beginning of each of the two consecutive months.

[0052] 20. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to sections 16, 17, 18 and / or 19, wherein said fixed dose is orally administered to said patient, preferably divided into individual amounts of a daily dose to be administered to said patient on 2 to 7 days during said week or on 2 to 7 days of each of said weeks, more preferably in approximately equal doses.

[0053] 21. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to sections 16, 17, 18, 19 and / or 20, wherein the fixed dose is orally administered to the patient within 2 to 7 days during the week or within 2 to 7 days of each of these weeks, preferably divided into individual amounts of the daily dose, preferably approximately equal doses.

[0054] Thus, a treatment year typically consists of 2 months of active treatment, i.e. 2 months in which cladribine is administered to the patient, and 10 months of no active treatment, i.e. 10 months in which cladribine is not administered to the patient. Preferably, 2 months of active treatment mark the beginning of the treatment year. Preferably, cladribine is administered to the patient during the first week of each of the two months of active treatment.

[0055] 22. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein said cladribine is to be orally administered to each patient at said fixed dose per patient, per unit body weight and per treatment year, preferably as described in the above and / or below numbered sections, and wherein the treatment comprises one or more additional treatment years. Preferably, cladribine for use as described herein is administered during two or more treatment years, more preferably 2 treatment years, preferably said treatment years are preferably substantially identical adjacent treatment years.

[0056] However, depending on the patient's blood status, it may become necessary or advantageous to separate the two treatment years by an interval, i.e. a determined time at which the previous treatment year ends and it is foreseen that the next treatment year cannot or should not start. Preferably and intentionally, no cladribine is administered during such an interval. Typically, in this respect, the interval lasts between 1 month and 8 months, preferably between 1 month and 6 months, more preferably between 1 month and 3 months. Frequently, the patient's blood status is monitored during such an interval to decide when the next treatment year can be started.

[0057] 23. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to one or more of the preceding sections, wherein said cladribine is to be orally administered to each patient at said fixed dose per patient, per unit body weight and per treatment year, preferably as described in the above and / or below numbered sections, and wherein the treatment comprises two treatment years, preferably comprises two essentially identical treatment years.

[0058] 24. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to sections 20 and / or 21, wherein the two treatment years are either directly adjacent to each other or separated by an interval of 1 to 10 months. Typically, such an interval, if present, is induced by the patient's blood state at the end of each treatment year before starting a new or subsequent treatment year. Sometimes, it may become necessary or advantageous to separate two treatment years by an interval, i.e. a determined time at which the previous treatment year ends and it is foreseen that the next treatment year cannot or should not start. Preferably and intentionally, cladribine is not administered during such an interval.

[0059] 25. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein said Cladribine is to be orally administered to each patient at a fixed dose per patient, per unit body weight and per treatment year, a) wherein the fixed dose per treatment year is selected from the range of 1.5 mg / kg to 4.0 mg / kg, preferably from the range of 1.5 mg / kg to 2.0 mg / kg, and particularly preferably is 1.75 mg / kg per treatment year for each patient, with a maximum deviation of + / - 0.2 mg / kg, b) where the treatment years include: (i) a 2-month treatment cycle starting in said treatment year, wherein said fixed dose of cladribine divided into daily doses of 5 to 20 mg cladribine is orally administered from about 1 to about 7 days of each month, preferably from about 1 to about 7 days of each month at the beginning of each month, and (ii) a duration of at least 10 months or a cladribine-free period of 10 months during which cladribine is not administered.

[0060] 26. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein said Cladribine is to be orally administered to each patient at a fixed dose per patient, per unit body weight and per treatment year, a) wherein the fixed dose per treatment year is selected from the range of 1.5 mg / kg to 4.0 mg / kg, preferably from the range of 1.5 mg / kg to 2.0 mg / kg, and particularly preferably is 1.75 mg / kg per treatment year for each patient, with a maximum deviation of + / - 0.2 mg / kg, b) where the treatment years include: (i) a 2-month treatment cycle starting in said treatment year, wherein said fixed dose of cladribine is orally administered on days 3 to 5 of each month at the beginning of each month, said fixed dose being divided into daily doses of 10 or 20 mg cladribine, (ii) a duration of at least 10 months or a cladribine-free period of 10 months during which cladribine is not administered.

[0061] 27. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the oral treatment is of patients with primary progressive multiple sclerosis and / or patients with secondary progressive multiple sclerosis, wherein the cladribine is to be orally administered to each patient at a fixed dose per patient, per unit of body weight and per treatment year, wherein the fixed dose per patient is preferably 1.75 mg / kg per treatment year for each patient with a maximum deviation of + / - 0.2 mg / kg, and wherein the treatment comprises at least two treatment years, preferably two or three treatment years.

[0062] 28. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the treatment comprises two treatment years either substantially adjacent to each other or separated by an interval of 1 to 10 months, preferably 1 to 6 months and in particular 1 to 3 months.

[0063] 29. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the treatment additionally comprises subsequent treatment years, a) wherein the fixed dose per treatment year is selected from the range of 0.75 mg / kg to 2.0 mg / kg, preferably from the range of 1.0 mg / kg to 1.5 mg / kg, and particularly preferably is 0.8 mg / kg per treatment year for each patient with a maximum deviation of + / - 0.2 mg / kg, b) where the subsequent treatment years include: (i) a 1-month or 2-month treatment cycle starting in said treatment year, wherein said fixed dose of cladribine is orally administered on days 3 to 5 of each month at the beginning of each month, said fixed dose being divided into daily doses of 10 or 20 mg of cladribine, (ii) a cladribine-free period lasting 11 or 10 months, respectively, during which cladribine was not administered.

[0064] 30. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to one or more of the preceding sections, wherein the treatment comprises one or two treatment years as described in the above and / or below sections, preferably 2 treatment years as described in the above and / or below sections, optionally plus an additional subsequent treatment year as described in section 26 or 29, followed by at least one year, preferably at least 2 years, in which Cladribine is not administered to the patient.

[0065] 31. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein said Cladribine is to be administered orally in liquid, tablet or capsule form.

[0066] 32. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described according to one or more of the preceding sections, wherein the cladribine is administered orally in the form of a tablet, preferably a tablet comprising about 10 mg of cladribine.

[0067] 33. Cladribine for use as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the cladribine is administered orally in the form of a tablet comprising 10 mg of cladribine in the form of a mixture of cladribine, 2-hydroxypropyl-β-cyclodextrin and cladribine-2-hydroxypropyl-β-cyclodextrin complex, wherein the weight ratio of cladribine to 2-hydroxypropyl-β-cyclodextrin is between about 1:10 and about 1:16, preferably between 1:13 and 1:15.

[0068] 34. A method of treating a patient diagnosed with a progressive form of multiple sclerosis, the method comprising: orally administering to the patient, preferably to each of the patients, a cumulative dose of about 3.5 mg / kg body weight of cladribine over 2 years (i.e. two treatment years), with a maximum deviation of + / - 0.4 mg / kg, in a course of about 1.75 mg / kg + / - 0.2 mg / kg per year (i.e. per treatment year), wherein each course consists of 2 treatment weeks, one at the beginning of the first month of each treatment year, and one at the beginning of the second month of each treatment year.

[0069] 35. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described in section 34, wherein each treatment week consists of 4 or 5 days on which the patient receives 10 mg or 20 mg of cladribine for oral administration, preferably as a single daily dose, depending on the body weight of the individual patient.

[0070] 36. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to section 35, wherein the patient receives 10 mg or 20 mg of cladribine for oral administration in the form of a tablet or capsule, preferably a tablet or capsule containing 10 mg of cladribine.

[0071] 37. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to section 36, wherein the patient receives 10 mg or 20 mg of cladribine for oral administration in the form of a tablet or capsule comprising 10 mg of cladribine in the form of a mixture of cladribine, 2-hydroxypropyl-β-cyclodextrin and cladribine-2-hydroxypropyl-β-cyclodextrin complex, wherein the weight ratio of cladribine to 2-hydroxypropyl-β-cyclodextrin is between about 1:10 and about 1:16, preferably between 1:13 and 1:15.

[0072] 38. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of sections 34 to 37, wherein the progressive form of multiple sclerosis is primary progressive multiple sclerosis.

[0073] 39. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of sections 34 to 37, wherein the progressive form of multiple sclerosis is secondary progressive multiple sclerosis.

[0074] 40. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of sections 34 to 37, wherein the progressive form of multiple sclerosis is selected from primary progressive multiple sclerosis and secondary progressive multiple sclerosis, the method comprising: The patient is orally administered a cumulative dose of about 3.5 mg / kg body weight of cladribine over 2 years, administered in 1 course of about 1.75 mg / kg, wherein each course consists of 2 treatment weeks, one at the beginning of the first month of each treatment year and one at the beginning of the second month of each treatment year.

[0075] 41. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to section 40, wherein each treatment week consists of 4 or 5 days on which the patient receives 10 mg or 20 mg cladribine for oral administration, preferably as a single daily dose, and preferably depending on the body weight of the individual patient.

[0076] 42. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated is between 18 and 65 years old, preferably inclusive.

[0077] 43. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated is between 18 and 51 years old, preferably including the endpoints.

[0078] 44. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated is between 12 and 51 years old, preferably including the endpoints.

[0079] 45. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated is a patient of female gender and / or a patient of male gender. Since female patients are more often affected by progressive forms of multiple sclerosis and / or are often more severely affected by them, a preferred aspect of the invention in this respect is the treatment of female patients.

[0080] 46. ​​A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated has not been treated with cladribine and / or a disease-modifying drug other than cladribine.

[0081] 47. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient is a patient who has previously received cladribine and / or a disease-modifying drug other than cladribine. Preferably, in this aspect, disease-modifying drugs other than cladribine include interferon beta-1a, beta interferon-1a (e.g., ).

[0082] 48. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated is additionally receiving one or more disease modifying drugs other than cladribine. Preferably, in this aspect, disease modifying drugs other than cladribine include interferon beta-1a, beta interferon-1a (e.g., ).

[0083] 49. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the disease modifying drug other than cladribine is selected from: interferon beta-1a, beta interferon-1a (e.g., ), Interferon beta-1b, interferon beta-1b (e.g., ), Pegylated interferon beta 1a (e.g. ), Alemtuzumab (eg, ), Daclizumab (eg, ), Dimethyl fumarate (e.g. ), Fingolimod (eg, ), Glatiramer acetate (eg, ), Natalizumab (eg, ),and Teriflunomide (e.g., ).

[0084] 50. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein after completing said 2 years with said 2 courses of treatment, cladribine is not administered to the patient within the subsequent 1 year or 2 years after completing said 2 years with said 2 courses of treatment.

[0085] 51. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein for patients who have each completed one year of said 2 courses of treatment, no additional cladribine treatment is required and / or no additional cladribine treatment is administered to said patient in the subsequent 3rd and 4th years.

[0086] 52. A method of treating a patient suffering from a progressive form of multiple sclerosis comprising orally administering to said patient tablets or capsules each containing about 10 mg of cladribine, wherein said tablets or capsules are administered during a cycle, referred to as a treatment year, comprising the following therapy: (i) a course of treatment lasting 2 months, wherein cladribine tablets or capsules are orally administered to the patient daily at a daily dose of 10 or 20 mg cladribine on 3 to up to 6 days of each month, preferably on 4 or 5 days of each month, preferably in the 1st week of each month (each treatment week); (ii) followed by a cladribine-free period lasting 10 months, preferably until the end of the first treatment year, wherein no cladribine is administered to the patient; Among them, patients with the following weights: - In the range of 40 to less than 50 kg, the following are or will be administered: 1) In the first month or treatment week of the course of treatment, 4 tablets or capsules (40 mg cladribine), 2) 4 tablets or capsules (40 mg cladribine) in the second month or treatment week of the course of treatment, - In the range of 50 to less than 60 kg, the following are administered or will be administered: 1) 5 tablets or capsules (50 mg cladribine) in the first month or treatment week of the course of treatment, 2) 5 tablets or capsules (50 mg cladribine) in the second month or treatment week of the course of treatment, - In the range of 60 to less than 70 kg, the following are or will be administered: 1) In the first month or treatment week of the course of treatment, 6 tablets or capsules (60 mg cladribine), 2) 6 tablets or capsules (60 mg cladribine) in the second month or treatment week of the course of treatment, - In the range of 70 to less than 80 kg, the following are administered or will be administered: 1) In the first month or treatment week of the course of treatment, 7 tablets or capsules (70 mg cladribine), 2) In the second month or treatment week of the course of treatment, 7 tablets or capsules (70 mg cladribine), - In the range of 80 to less than 90 kg, the following are or will be administered: 1) In the first month or treatment week of the course of treatment, 8 tablets or capsules (80 mg cladribine), 2) In the second month or treatment week of the course of treatment, 7 tablets or capsules (70 mg cladribine), - In the range of 90 to less than 100 kg, the following are or will be administered: 1) In the first month or treatment week of the course of treatment, 9 tablets or capsules (90 mg cladribine), 2) In the second month or treatment week of the course of treatment, 8 tablets or capsules (80 mg cladribine), - In the range of 100 to less than 110 kg, the following are administered or will be administered: 1) In the first month or treatment week of the course of treatment, 10 tablets or capsules (100 mg cladribine), 2) In the second month or treatment week of the course of treatment, 9 tablets or capsules (90 mg cladribine), - In the range of 110 kg and above, the following are applied or will be applied: 1) In the first month or treatment week of the course of treatment, 10 tablets or capsules (100 mg cladribine), 2) In the second month or treatment week of the course of treatment, 10 tablets or capsules (100 mg cladribine).

[0087] 53. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to section 52, wherein the method further comprises at least one subsequent period referred to as an additional treatment year, wherein the additional treatment year is substantially the same or preferably the same as the therapy referred to as a treatment year. Preferably, cladribine is administered during two or more treatment years, more preferably 2 treatment years, preferably these treatment years are preferably substantially identical adjacent treatment years.

[0088] However, depending on the patient's blood status, it may become necessary or advantageous to separate the two treatment years by an interval, i.e. a determined time at which the previous treatment year ends and it is foreseen that the next treatment year cannot or should not start. Preferably and intentionally, no cladribine is administered during such an interval. Typically, in this respect, the interval lasts between 1 month and 8 months, preferably between 1 month and 6 months, more preferably between 1 month and 3 months. Frequently, the patient's blood status is monitored during such an interval to decide when the next treatment year can be started.

[0089] 54. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to section 53, wherein the additional treatment year is directly adjacent to the therapy referred to as a treatment year, or there is an interval of 1 to 10 months between two treatment years. Typically, such an interval, if present, is induced by the patient's blood state at the end of each treatment year before starting a new or subsequent treatment year. Sometimes, it may become necessary or advantageous to separate two treatment years by an interval, i.e. a determined time when the previous treatment year ends and it is foreseen that the next treatment year cannot or should not start. Preferably and intentionally, cladribine is not administered during such an interval.

[0090] 55. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to section 52 or 53, wherein the method further comprises more than one subsequent period, referred to as additional treatment years, preferably two additional treatment years, wherein all said additional treatment years are substantially the same or preferably the same, and wherein said additional treatment years are directly adjacent to each other, or there is a gap of 1 to 10 months between at least two of these additional treatment years.

[0091] 56. A method of treating a patient suffering from a progressive form of multiple sclerosis comprising orally administering to said patient tablets or capsules each containing about 10 mg of cladribine, wherein said tablets or capsules are administered during a cycle known as a treatment year according to a regimen comprising: (i) a first course of treatment lasting 2 months, wherein cladribine tablets or capsules are orally administered daily at a daily dose of 10 or 20 mg cladribine on 3 to up to 6 days of each month, preferably on 4 or 5 days of each month, preferably in the 1st week (treatment week) of each month; (ii) followed by a first cladribine-free period lasting 10 months, preferably until the end of the first treatment year, wherein no cladribine is administered to the patient; (iii) followed by a second course of treatment lasting 2 months, wherein cladribine tablets or capsules are orally administered daily at a daily dose of 10 or 20 mg cladribine on 3 to up to 6 days of each month, preferably on 4 or 5 days of each month, preferably in the 1st week (treatment week) of each month; and (iv) followed by a second cladribine-free period lasting 10 months, preferably until the end of the second treatment year, wherein no cladribine is administered to the patient, and Among them, patients with the following weights: - In the range of 40 to less than 50 kg, the following are administered or will be administered: 1) 4 tablets or capsules (40 mg cladribine) in the first month or treatment week of both the first and second cycles of treatment, respectively, 2) 4 tablets or capsules (40 mg cladribine) in the second month or treatment week of both the first and second cycles of treatment, respectively, - In the range of 50 to less than 60 kg, the following are administered or will be administered: 1) 5 tablets or capsules (50 mg cladribine) in the first month or treatment week of both the first and second cycles of treatment, respectively, 2) 5 tablets or capsules (50 mg cladribine) in the second month or treatment week of both the first and second cycles of treatment, respectively, - In the range of 60 to less than 70 kg, the following are or will be administered: 1) 6 tablets or capsules (60 mg cladribine) in the first month or treatment week of both the first and second cycles of treatment, respectively, 2) 6 tablets or capsules (60 mg cladribine) in the second month or treatment week of both the first and second cycles of treatment, respectively, - In the range of 70 to less than 80 kg, the following are administered or will be administered: 1) 7 tablets or capsules (70 mg cladribine) in the first month or treatment week of both the first and second cycles, 2) 7 tablets or capsules (70 mg cladribine) in the second month or treatment week of both the first and second cycles of treatment, respectively, - In the range of 80 to less than 90 kg, the following are or will be administered: 1) 8 tablets or capsules (80 mg cladribine) in the first month or treatment week of both the first and second cycles of treatment, respectively, 2) 7 tablets or capsules (70 mg cladribine) in the second month or treatment week of both the first and second cycles of treatment, respectively, - In the range of 90 to less than 100 kg, the following are or will be administered: 1) 9 tablets or capsules (90 mg cladribine) in the first month or treatment week of both the first and second cycles, respectively, 2) 8 tablets or capsules (80 mg cladribine) in the second month or treatment week of both the first and second cycles of treatment, respectively, - In the range of 100 to less than 110 kg, the following are administered or will be administered: 1) 10 tablets or capsules (100 mg cladribine) in the first month or treatment week of both the first and second cycles, 2) 9 tablets or capsules (90 mg cladribine) in the second month or treatment week of both the first and second cycles, respectively, - In the range of 110 kg and above, the following are applied or will be applied: 1) 10 tablets or capsules (100 mg cladribine) in the first month or treatment week of both the first and second cycles, 2) 10 tablets or capsules (100 mg cladribine) in the second month or treatment week of both the first and second cycles.

[0092] 57. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably as described in the preceding sections, wherein the 10 mg or 20 mg of cladribine for oral administration is administered to the patient in the form of a tablet or capsule comprising 10 mg of cladribine in the form of a mixture of cladribine, 2-hydroxypropyl-β-cyclodextrin and cladribine-2-hydroxypropyl-β-cyclodextrin complex, wherein the weight ratio of cladribine to 2-hydroxypropyl-β-cyclodextrin is between about 1:10 and about 1:16, preferably between 1:13 and 1:15.

[0093] 58. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the progressive form of multiple sclerosis is primary progressive multiple sclerosis.

[0094] 59. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the progressive form of multiple sclerosis is secondary progressive multiple sclerosis.

[0095] 60. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated is between 18 and 51 years old or between 12 and 51 years old.

[0096] 61. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated is a patient of female gender and / or a patient of male gender. Since female patients are more often affected by progressive forms of multiple sclerosis and / or are often more severely affected by them, a preferred aspect of the invention in this respect is the treatment of female patients.

[0097] 62. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated has not been treated with cladribine and / or a disease-modifying drug other than cladribine.

[0098] 63. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient is a patient who has previously received cladribine and / or a disease-modifying drug other than cladribine.

[0099] 64. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated is additionally receiving one or more disease-modifying drugs other than cladribine.

[0100] 65. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the disease modifying drug other than cladribine is selected from: interferon beta-1a, beta interferon-1a (e.g., ), Interferon beta-1b, interferon beta-1b (e.g., ), Pegylated interferon beta 1a (e.g. ), Alemtuzumab (eg, ), Daclizumab (eg, ), Dimethyl fumarate (e.g. ), Fingolimod (eg, ), Glatiramer acetate (eg, ), Natalizumab (eg, ),and Teriflunomide (e.g., ).

[0101] 66. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein after completing said 2 years with said 2 courses of treatment, cladribine is not administered to the patient within the subsequent 1 year or 2 years after completing said 2 years with said 2 courses of treatment.

[0102] 67. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein for patients who have completed the 2 treatment courses of one year each, no additional cladribine treatment is required and / or no additional cladribine treatment is administered to the patient in the subsequent 3rd and 4th years.

[0103] 68. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated has preferably been diagnosed with a progressive form of multiple sclerosis, preferably selected from primary progressive multiple sclerosis and secondary progressive multiple sclerosis, before starting treatment according to the method.

[0104] 69. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated has preferably been diagnosed with primary progressive multiple sclerosis before starting treatment according to the method.

[0105] 70. A method as described herein, preferably as described in one or more of the above and / or below numbered sections, and more preferably according to one or more of the preceding sections, wherein the patient to be treated has preferably been diagnosed with secondary progressive multiple sclerosis before starting treatment according to the method.

[0106] 71. A method as described in one or more of the above and / or below numbered sections and preferably according to one or more of the preceding sections, wherein the patient has high disease activity (HDA) and / or has been diagnosed with high disease activity. Preferably, cladribine is used according to the invention for patients who have been diagnosed with high disease activity before starting treatment.

[0107] Alternatively, preferred are methods of treatment as described herein and in particular as described in the above sections numbered 1 to 71, wherein one or more of the following given preferred features are achieved: The induction period lasts up to about 2 months. The cladribine-free period (ii) lasts about 10 months, about 12 months, about 14 months or about 16 months, preferably about 10 months; ● A cladribine-free cycle (iv) lasts for at least 10 months, at least 14 months, at least 22 months, or at least 32 months, or a cladribine-free cycle (iv) lasts for about 10 months, about 14 months, about 22 months, or about 32 months; The total dose of cladribine achieved at the end of the induction period is about 1.75 mg / kg, or the total dose of cladribine achieved at the end of the induction period is about 3.5 mg / kg, preferably about 1.75 mg / kg; The total dose of cladribine achieved at the end of the maintenance period is about 1.75 mg / kg, or the total dose of cladribine achieved at the end of the maintenance period is about 3.5 mg / kg, preferably about 1.75 mg / kg; The total cladribine dose achieved at the end of the induction period is about 1.75 mg / kg and the total cladribine dose achieved at the end of the maintenance period is about 1.75 mg / kg; The cumulative total dose of cladribine achieved after completion of both the induction and maintenance cycles was approximately 3.5 mg / kg; ● A cladribine-free period (ii) lasting up to about 10 months, or a cladribine-free period (ii) lasting at least about 10 months if East End does complete Isa; The cladribine-free period (ii) lasts at least about 10 months, typically 10 to 13 months, and in particular about 10 months; A cladribine (iv)-free period lasting at least about 8 months, more preferably at least about 10 months, even more preferably at least 18 months, and especially at least 24 months; ● The cladribine-free period (iv) lasts for at least about 10 months or at least 10 months; A cladribine (iv)-free period lasting at least about 8 months, more preferably at least about 10 months, even more preferably at least 18 months, and especially at least 24 months; ●Cladribine-free cycles (iv) lasting up to about 34 months, up to 20 months, up to 13 months, or up to 10 months; ● No cladribine cycle (ii) and / or (iv) without any administration, more preferably without any administration of MS therapy; A maintenance period lasting up to about 4 months, or up to about 3 months, or up to about 2 months, preferably up to about 2 months; ●Maintenance therapy lasts about two months; • Steps (iii) to (iv) are repeated at least once or twice.

[0108] It is to be understood that only two or more than two of the above given features may be combined without contradicting each other.

[0109] definition "Total dose" or "cumulative dose" preferably refers to the total dose of cladribine administered during the treatment, i.e. the dose reached at the end of the treatment calculated by adding the daily doses. For example, the total dose of cladribine corresponding to a treatment of 0.7 mg / kg cladribine per day during 5 days is 3.5 mg / kg, or the total dose of cladribine corresponding to a treatment of 0.35 mg / kg cladribine per day during 5 days is 1.7 mg / kg.

[0110] "Total effective dose" or "cumulative effective dose" preferably refers to the bioavailable dose of cladribine after a given administration cycle, i.e. the bioavailable dose achieved at the end of the treatment 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 cladribine per day during 5 days, where the bioavailability of cladribine is about 40%, is 1.4 mg / kg; or the total effective dose of cladribine corresponding to a treatment of 0.35 mg / kg cladribine per day during 5 days, where the bioavailability of cladribine is about 40%, is 0.7 mg / kg.

[0111] Typically, the bioavailability of cladribine or the bioavailability of a cladribine formulation used in the context of the present invention is from about 30% to about 90%, preferably from about 40% to about 60%, such as about 50%.

[0112] "One week" preferably refers to a time period of about 5, about 6 or about 7 days.

[0113] "One month" preferably refers to a time period of about 28, about 29, about 30 or about 31 days.

[0114] As used herein, "treatment" preferably comprises a continuous series of "induction therapy" and at least one "maintenance therapy". Typically, treatment according to the present invention comprises an "induction therapy" and about one or about two or about three maintenance therapies, preferably one or two maintenance therapies, more preferably one maintenance therapy.

[0115] Typically, treatment according to the invention is for about 2 years (about 24 months), or about 3 years (about 36 months), or about 4 years (about 48 months).

[0116] "Induction therapy" preferably consists of a continuous series of: (i) an induction cycle, in which cladribine or a pharmaceutical formulation of cladribine of the present invention is orally administered, and (ii) a cladribine-free cycle. The induction cycle preferably lasts up to about 4 months, or up to about 3 months, or up to about 2 months. For example, the induction cycle lasts from about 2 to about 4 months. The induction cycle preferably consists of oral administration of cladribine or a pharmaceutical formulation thereof during about 1 to about 7 days in each month.

[0117] A "cladribine-free cycle" is preferably a cycle in which cladribine is not administered to the patient. During the cladribine-free cycle, the patient may not have any administration, or may be administered with a placebo pill or another drug in addition to cladribine. The cladribine-free cycle preferably lasts up to about 10 months, or up to 9 months, or up to about 8 months. For example, the cladribine-free cycle lasts from about 8 to about 10 months, typically at least about 8 months. More preferably, the cladribine-free cycle lasts at least about 8 months, at least about 9 months, or at least about 10 months. Particularly preferably, the cladribine-free cycle lasts about 10 months. However, if recommended by a physician, the cladribine-free cycle may also be preferably extended, preferably by 1-3 months. The durations given for the cladribine-free cycle in this section are particularly preferred for the cladribine-free cycle between induction therapy and maintenance therapy. For the cladribine-free cycle after maintenance therapy, a duration of at least about 10 months, at least 22 months, or at least 34 months is preferred. Typically, the cladribine-free period following maintenance therapy will be between about 10 months and about 22 months.

[0118] "Maintenance therapy" preferably consists of a continuous series of: (i) maintenance cycles, in which cladribine or a cladribine pharmaceutical formulation of the invention is orally administered at a dose lower than or equal to the dose of cladribine orally administered during the induction therapy cycle, and (ii) a cladribine-free cycle. The maintenance cycle preferably lasts up to about 4 months, or up to about 3 months, or up to about 2 months, preferably up to about 2 months. For example, the maintenance cycle lasts from about 2 to about 4 months, preferably for about 2 months. The maintenance cycle comprises oral administration of cladribine or a pharmaceutical formulation thereof during about 1 to about 7 days of each month.

[0119] Within the context of the present invention, beneficial effects may be seen after one or more "treatments", after "induction therapy", after "maintenance therapy" or during a cladribine-free period, and the beneficial effects preferably include but are not limited to one or more selected from the following: attenuation, reduction, reduction or elimination of the development of pathology following disease onset.

[0120] "Daily dose" preferably refers to the total dose of cladribine orally administered to a patient per administration day. The daily dose may be achieved by a single or multiple administrations per day, such as, for example, once a day, twice a day or three times a day. Preferably, it is achieved or realized by a single administration per day, preferably consisting of one or more tablets or capsules, preferably as described herein.

[0121] Preferably, the dosage administered to an individual in a single or multiple dosage form will vary depending on various factors, including pharmacokinetic properties, patient conditions and characteristics (sex, age, weight, health, size), symptom severity, concurrent treatment, treatment frequency, and desired effect. Preferably, the administered dosage (dosage / dose) will vary only by one factor, i.e., the weight of each individual, patient, or human being. A dosage of about 1.75 mg per kg body weight of each individual, patient, or human being is preferred for each induction cycle and each maintenance cycle. Preferably, the dosage of about 1.75 mg per kg body weight includes a deviation of plus or minus 10%, preferably a deviation of plus or minus 5%. Typically, the deviation is caused by the dosage strength of each cladribine-containing dosage form (e.g., 10 mg tablet or capsule) to be administered to each individual, patient, or human being, and / or the weight range of each individual, patient, or human being is preferably divided into, for example, a weight range of about 5 kg or about 10 kg, to provide sufficient guidance and practicality for administering such a fixed dose according to the weight of the individual, patient, or human being.

[0122] Patients with MS can be defined, for example, as having clinically definite or laboratory definite MS according to the Schumacher or Poser criteria (Schumacher et al., 1965, Ann. NY Acad. Sci. 1965; 122:552-568; Poser et al., 1983, Ann. Neurol. 13(3):227-31).

[0123] "Relapses" preferably involve neurological problems that occur over short periods, typically over days, but sometimes in as little as hours or even minutes. These attacks most often involve movement, sensory, visual or coordination problems early in the disease. Later, bladder, bowel, sexual and cognitive problems may manifest. Sometimes, attacks occur over weeks. Typical MS relapses involve periods of worsening with the development of neurological deficits, followed by plateaus, in which the patient does not get better but also does not get any worse, followed by recovery periods. Recovery usually begins within a few weeks.

[0124] The "efficacy" of a treatment according to the invention may preferably be measured based on changes in the course of the disease in response to the use according to the invention. For example, efficacy of a treatment for MS may be measured by the frequency of relapses of RRMS and the presence or absence of new lesions in the CNS as detected using methods such as MRI techniques (Miller et al., 1996, Neurology, 47(Suppl 4):S217; Evans et al., 1997, Ann. Neurology, 41:125-132).

[0125] Preferably, the observation of reduction and / or inhibition of MRI T1 gadolinium-enhanced lesions (considered to represent active inflammatory areas) gives the primary efficacy variable. Secondary efficacy variables preferably include MRI T1-enhanced brain lesion volume, MRI T1-enhanced lesion number, MRI T2 lesion volume (considered to represent the total disease burden, i.e., demyelination, gliomatosis, inflammation, and axonal loss), MRI T1-enhanced low-intensity lesion volume (considered to represent mainly demyelination and axonal loss), MS time progression ratio, frequency and severity of deterioration, and time to deterioration ratio, expanded disability status scale score, and Scripps neurological grade scale (SNRS) score (Sipe et al., 1984, Neurology, 34, 1368-1372). Methods for early and accurate diagnosis of multiple sclerosis and disease progression after the disease is described in Mattson, 2002, Expert Rev. Neurotherapeutics, 319-328.

[0126] The degree of disability of MS patients can be measured, for example, by the Kurtzke Expanded Disability Status Scale (EDSS) score (Kurtzke, 1983, Neurology, 33, 1444-1452). Typically, a decrease in EDSS score corresponds to improvement of the disease, and conversely, an increase in EDSS score corresponds to worsening of the disease.

[0127] Cladribine (2-CdA) 2-CdA and its pharmaceutically acceptable salts can be used in the practice of the present invention.

[0128] Cladribine can be formulated into any pharmaceutical formulation suitable for oral administration. Representative oral formulations of 2-CdA are described in (WO 96 / 19230; WO 96 / 19229; US 6,194,395; US 5,506,214; WO 2004 / 087100; WO2004 / 087101), the contents of which are incorporated herein by reference. Examples of ingredients for oral formulations are given below.

[0129] Methods for preparing 2-CdA are well known in the art. For example, the preparation of 2-CdA is described in (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 from Bedford Laboratories, Bedford, Ohio.

[0130] Oral administration of cladribine may be in the form of capsules, tablets, oral suspensions or syrups. Tablets or capsules may contain about 3 to 500 mg of cladribine. Preferably, they may contain about 3 to about 10 mg of cladribine, more preferably about 3, about 5 or about 10 mg of cladribine. The capsule may be a gelatin capsule and, in addition to the amount of cladribine described above, may also contain a small amount of magnesium stearate or other excipients, such as less than 5% by weight. The tablet may contain the aforementioned amount of compound (cladribine) and a binder, which may be a gelatin solution, starch paste in water, polyvinyl alcohol in water, etc., with a typical sugar coating. Alternatively, the tablet may contain the aforementioned amount of compound (cladribine) and a binder, comprising or consisting of one or more cyclodextrins. Preferably, the binder is contained in the tablet in an amount of 50% or more, 60% or more, 70% or more, 80% or more or 90% or more, for example, about 60%, about 70%, about 80%, about 90% or about 95%, based on the total weight of the tablet. In addition, the tablet may contain one or more other excipients in an amount of less than 50% and preferably less than 40%, for example, about 40%, about 30%, about 20% or about 10%, based on the total weight of the tablet. Preferably, the one or more cyclodextrins contain 2-hydroxypropyl-β-cyclodextrin or consist essentially of 2-hydroxypropyl-β-cyclodextrin.

[0131] Composition The composition may further comprise one or more pharmaceutically acceptable additional ingredients, such as alum, stabilizers, antimicrobial agents, buffers, colorants, flavoring agents, adjuvants, and the like.

[0132] The composition 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 binders, fillers, lubricants, disintegrants, and wetting agents. Binders include but are not limited to syrups, gum arabic, gelatin, sorbitol, tragacanth, mucilage of starch, and polyvinylpyrrolidone. Fillers include but are not limited to lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate, and sorbitol. Lubricants include but are not limited to magnesium stearate, stearic acid, talc, polyethylene glycol, and silicon dioxide. Disintegrants include but are not limited to potato starch and sodium starch glycolate. Wetting agents include but are not limited to sodium lauryl sulfate. Tablets may be coated according to methods well known in the art.

[0133] The composition may also be a liquid preparation, including (but not limited to): aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. The composition may also be formulated as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid preparations may contain additives, including (but not limited to) suspending agents, emulsifiers, non-aqueous vehicles and preservatives. Suspending agents include (but not limited to) sorbitol syrup, methylcellulose, glucose / sucrose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and edible hydrogenated fats. Emulsifiers include (but not limited to) lecithin, sorbitan monooleate and gum arabic. Non-aqueous vehicles include (but not limited to) edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol and ethanol. Preservatives include (but not limited to) methyl or propyl paraben and sorbic acid.

[0134] combination Preferably, cladribine may be administered prophylactically or therapeutically to an individual in a therapeutically effective amount alone or in combination with IFN-β prior to, concurrently with, or sequentially with other therapeutic therapies or agents (e.g., multiple drug therapies), particularly therapeutic agents for the treatment of multiple sclerosis. Active agents administered concurrently with other therapeutic agents may be administered in the same or different compositions and may be administered by the same or different routes of administration.

[0135] For example, when cladribine is administered in combination with IFN-β, it is preferred that IFN-β be administered during cladribine-free cycles.

[0136] Alternatively, when Cladribine is administered in combination with IFN-β, the IFN-β is preferably administered after the "treatment" according to the present invention.

[0137] As used herein, the term "interferon-β (IFN-β)" is preferably intended to include fibroblast interferons, in particular of human origin, as obtained by isolation from biological fluids, or as obtained from prokaryotic or eukaryotic host cells by DNA recombinant technology, as well as salts, functional derivatives, variants, analogs and active fragments thereof.

[0138] Preferably, IFN-β suitable for use according to the invention is commercially available, for example as (Serono), (Biogen) or (Schering). According to the present invention, the use of human interferon is also preferred. As used herein, the term interferon is intended to cover its salts, functional derivatives, variants, analogs and active fragments.

[0139] (recombinant human interferon-β) is one of the latest developments in interferon therapy for multiple sclerosis (MS) and is believed to represent a significant advance in MS therapy. Interferon (IFN)-β1a is produced by a mammalian cell line. Interferon β-1a, given subcutaneously three times a week, has been determined to be effective for treating relapsing-remitting multiple sclerosis (RRMS). Interferon β-1a may have a positive effect on the long-term course of MS by reducing the number and severity of relapses and reducing disease burden and disease activity as measured by MRI.

[0140] If applicable, the dosage of IFN-[beta] for treating progressive forms of MS according to the invention preferably depends on the type of IFN-[beta] used.

[0141] If it is feasible according to the invention, in the case where IFN is produced in E. coli under the trademark In the case of commercially available recombinant IFN-β1b, it may be preferably administered subcutaneously every two days at a dose of about 250 to 300 μg or 8 MIU to 9.6 MIU per person.

[0142] If feasible according to the invention, in the case where IFN is produced in Chinese Hamster Ovary cells (CHO cells) under the trademark In the case of commercially available recombinant IFN-β1a, it may be preferably administered intramuscularly once a week at a dose of about 30 μg to 33 μg or 6 MIU to 6.6 MIU per person.

[0143] According to the present invention, IFN is produced in Chinese hamster ovary cells (CHO cells) under the trademark When commercially available recombinant IFN-β1a is used, it may be preferably administered subcutaneously three times a week (TIW) at a dose of 22 to 44 μg or 6 MIU to 12 MIU per person.

[0144] patient Preferably, the patients according to the present invention are patients suffering from primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and early secondary progressive multiple sclerosis (ESPMS), preferably primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS).

[0145] Particularly preferably, the patient according to the present invention is a patient diagnosed with primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and early secondary progressive multiple sclerosis (ESPMS), preferably primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS). The diagnostic criteria are known to those skilled in the art and are further described in the various sections herein.

[0146] Thus, preferably, the patient according to the present invention does not suffer from, or has not been diagnosed with, RRMS and / or ESPMS. More preferably, the patient to be treated according to the present invention is diagnosed with a form of MS other than RRMS and / or ESPMS, or is diagnosed with a form of MS other than a relapsing form of MS.

[0147] Preferably, according to the present invention, the patient is selected from human males or females aged between 10 and 70 years, more preferably between 18 and 65 years, even more preferably between 18 and 55 years, and especially between 18 and 51 years. Since female patients make up the majority and usually have a higher disease burden, the treatment of female patients is preferred.

[0148] Alternative uses according to the invention In one embodiment, the present invention provides the use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive forms of multiple sclerosis, preferably PPMS and / or SPMS, wherein the formulation is to be orally administered according to the following consecutive steps: (i) an induction cycle, wherein the pharmaceutical formulation of cladribine is administered, and wherein the total dose of cladribine achieved at the end of the induction cycle is from about 1.7 mg / kg to about 3.5 mg / kg; (ii) no cladribine cycle, in which cladribine was not administered; (iii) a maintenance cycle, wherein the cladribine pharmaceutical formulation is administered, and wherein the total dose of cladribine achieved at the end of the maintenance cycle is less than or equal to the total dose of cladribine achieved at the end of the induction cycle (i); (iv) Cladribine-free cycles, in which no cladribine is administered.

[0149] In another embodiment the invention provides the use according to the invention, wherein the induction period lasts up to about 4 months, or up to about 3 months, or up to about 2 months.

[0150] In another embodiment the invention provides the use according to the invention, wherein the induction period lasts up to about 2 months.

[0151] In another embodiment the invention provides the use according to the invention, wherein the induction period lasts up to about 4 months.

[0152] In another embodiment, the present invention provides the use according to the invention, wherein the cladribine-free period (ii) lasts about 10 months, about 12 months, about 14 months or about 16 months.

[0153] In another embodiment, the present invention provides the use according to the invention, wherein the cladribine-free period (iv) lasts about 10 months, about 14 months, about 22 months or about 32 months.

[0154] In another embodiment the invention provides the use according to the invention, wherein the total dose of cladribine achieved at the end of the induction period is about 1.75 mg / kg.

[0155] In another embodiment the invention provides the use according to the invention, wherein the total dose of cladribine achieved at the end of the induction period is about 3.5 mg / kg.

[0156] In another embodiment the invention provides the use according to the invention, wherein the total dose of cladribine achieved at the end of the maintenance period is about 1.75 mg / kg.

[0157] In another embodiment, the present invention provides the use according to the invention, wherein the total dose of cladribine achieved at the end of the maintenance period is about 3.5 mg / kg, more preferably about 1.75 mg / kg.

[0158] In another further embodiment, the invention provides the use according to the invention, wherein the cladribine-free period lasts up to about 34 months, or up to 20 months, or up to 10 months. It is especially preferred for the cladribine-free period (iv).

[0159] In another further embodiment the present invention provides the use according to the present invention, wherein the cladribine-free (ii) period lasts up to about 8 months.

[0160] In another further embodiment the present invention provides the use according to the present invention, wherein the cladribine-free (ii) period lasts for at least about 8 months.

[0161] In another further embodiment, the present invention provides the use according to the invention, wherein the cladribine-free period (ii) lasts for at least about 10 months, typically 10 to 18 months, and in particular about 10 months.

[0162] In another further embodiment the present invention provides the use according to the present invention, wherein the cladribine (iv)-free period lasts for at least about 10 months.

[0163] In another further embodiment the present invention provides the use according to the invention, wherein the cladribine (iv)-free period lasts at least about 8 months, more preferably at least about 10 months, even more preferably at least 18 months, and in particular at least 24 months.

[0164] In another further embodiment, the present invention provides the use according to the invention, wherein the cladribine-free period (ii) and / or (iv) lasts at least about 8, more preferably at least 10 months, and typically about 10 months or about 10 to 18 months.

[0165] In another further embodiment the present invention provides the use according to the invention, wherein a placebo pill is administered during the cladribine-free period.

[0166] In another further embodiment the present invention provides the use according to the present invention, wherein the Cladribine-free period is free of any administration.

[0167] In another other embodiment, the present invention provides the use according to the present invention, wherein the maintenance period lasts up to about 4 months, or up to about 3 months, or up to about 2 months, preferably up to about 2 months.

[0168] In another further embodiment the present invention provides the use according to the present invention, wherein the total dose of cladribine achieved at the end of the maintenance period (iii) is about 1.75 mg / kg.

[0169] In yet another embodiment, the present invention provides the use according to the present invention, wherein steps (iii) to (iv) are repeated at least once or twice.

[0170] In this aspect, the cladribine-free period (iv) preferably lasts at least about 24 months, or at least about 18 months, or at least 12 months, or at least about 10 months, or at least about 9 months, or at least about 8 months.

[0171] In a preferred embodiment, the present invention provides the use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive forms of multiple sclerosis, preferably PPMS and / or SPMS, wherein the formulation is to be orally administered according to the following consecutive steps: (i) an induction cycle, wherein the pharmaceutical formulation of cladribine is administered, and wherein the total dose of cladribine achieved at the end of the induction cycle is from about 1.7 mg / kg to about 3.5 mg / kg; (ii) no cladribine cycle, in which cladribine was not administered; (iii) a maintenance cycle, wherein the cladribine pharmaceutical formulation is administered, and wherein the total dose of cladribine achieved at the end of the maintenance cycle is less than or about equal to, preferably about equal to, the total dose of cladribine achieved at the end of the induction cycle (i) (iv) a cladribine-free cycle, wherein cladribine is not administered; wherein the induction period lasts up to about 4 months, or up to about 3 months, or up to about 2 months; the cladribine-free period (ii) lasts up to about 10 months, or up to about 9 months, or up to about 8 months; the maintenance period (iii) lasts up to about 2 months; the cladribine-free period (iv) lasts up to about 10 months; the total cladribine dose achieved at the end of the maintenance period is about 1.7 mg / kg, and steps (iii) to (iv) are repeated once, twice, or three times.

[0172] In another embodiment, the present invention provides the use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive forms of multiple sclerosis, preferably PPMS and / or SPMS, wherein the formulation is to be orally administered according to the following consecutive steps: (i) an induction cycle, wherein the pharmaceutical formulation of cladribine is administered, and wherein the total effective dose of cladribine achieved at the end of the induction cycle is from about 0.7 mg / kg to about 1.4 mg / kg; (ii) no cladribine cycle, in which cladribine was not administered; (iii) a maintenance period, wherein the cladribine pharmaceutical formulation is administered, and wherein the total effective dose of cladribine achieved at the end of the maintenance period (iii) is less than or about equal to, preferably about equal to, the total effective dose of cladribine achieved at the end of the induction period (i); (iv) Cladribine-free cycles, in which no cladribine is administered.

[0173] In another embodiment, the present invention provides the use of cladribine for the preparation of a pharmaceutical formulation for the treatment of progressive forms of multiple sclerosis, preferably PPMS and / or SPMS, wherein the formulation is to be orally administered according to the following consecutive steps: (i) an induction cycle, wherein the pharmaceutical formulation of cladribine is administered, and wherein the total effective dose of cladribine achieved at the end of the induction cycle is from about 0.7 mg / kg to about 1.4 mg / kg; (ii) no cladribine cycle, in which cladribine was not administered; (iii) a maintenance cycle, wherein the cladribine pharmaceutical formulation is administered, and wherein the total effective dose of cladribine achieved at the end of the maintenance cycle is less than or equal to, preferably equal to, the total effective dose of cladribine achieved at the end of the induction cycle (i); (iv) a cladribine-free cycle, wherein cladribine is not administered; wherein the induction period lasts up to about 4 months, or up to about 3 months, or up to about 2 months; the cladribine-free period (ii) lasts up to about 10 months, or up to about 9 months, or up to about 8 months; the maintenance period (iii) lasts up to about 2 months; the cladribine-free period (ii) lasts up to about 10 months; the total effective dose of cladribine achieved at the end of the maintenance period is about 0.7 mg / kg, and steps (iii) to (iv) are repeated once, twice or three times.

[0174] In a preferred embodiment, the present invention provides cladribine for use as a medicament for the treatment of progressive forms of multiple sclerosis, preferably PPMS and / or SPMS, wherein the medicament is to be orally administered according to the following consecutive steps: (i) an induction cycle, wherein the pharmaceutical formulation of cladribine is administered, and wherein the total dose of cladribine achieved at the end of the induction cycle is from about 1.7 mg / kg to about 3.5 mg / kg, preferably about 1.75 mg / kg or about 3.5 mg / kg, more preferably about 1.75 mg / kg; (ii) no cladribine cycle, in which cladribine was not administered; (iii) a maintenance cycle, wherein the cladribine pharmaceutical formulation is administered, and wherein the total dose of cladribine achieved at the end of the maintenance cycle is less than or equal to the total dose of cladribine achieved at the end of the induction cycle (i); (iv) no cladribine cycle, in which cladribine was not administered; wherein the induction period lasts up to about 4 months, or up to about 3 months, or up to about 2 months; the cladribine-free period (ii) lasts up to about 10 months, or up to about 9 months, or up to about 8 months; the maintenance period (iii) lasts up to about 2 months; the cladribine-free period (iv) lasts up to about 10 months; the total cladribine dose achieved at the end of the maintenance period is about 1.75 mg / kg, and steps (iii) to (iv) are repeated once, twice, or three times.

[0175] In another embodiment, the present invention provides the use of cladribine according to the invention, wherein the pharmaceutical formulation is to be administered orally at a daily dose of cladribine of about 3 to 30 mg cladribine, preferably 5 to 20 mg cladribine, most preferably 10 mg cladribine.

[0176] In another further embodiment, the present invention provides the use according to the present invention, wherein the total dose of cladribine achieved at the end of the induction period is about 3.5 mg / kg and the total dose of cladribine achieved at the end of the maintenance period is about 1.75 mg / kg.

[0177] In another embodiment, the invention provides the use according to the invention, wherein the total dose of cladribine achieved at the end of the induction period is about 1.75 mg / kg and the total dose of cladribine achieved at the end of the maintenance period is about 1.75 mg / kg.

[0178] In another other embodiment, the present invention provides the use according to the present invention, wherein the total effective dose of cladribine achieved at the end of the induction period is about 1.4 mg / kg and the total effective dose of cladribine achieved at the end of the maintenance period is about 0.7 mg / kg.

[0179] In another embodiment, the present invention provides the use of cladribine according to the invention, wherein the pharmaceutical formulation is to be administered orally once a day during the induction cycle.

[0180] In another embodiment, the present invention provides the use of cladribine according to the invention, wherein the pharmaceutical preparation is to be orally administered several times a day, once a day, preferably twice or three times a day, more preferably twice a day during the induction cycle.

[0181] In another embodiment, the present invention provides the use of cladribine according to the invention whereby the pharmaceutical formulation is orally administered from about 1 day to about 7 days per month, preferably from about 5 days to about 7 days per month during the induction cycle.

[0182] In another embodiment, the present invention provides the use of cladribine according to the present invention whereby the pharmaceutical formulation is orally administered at about 0.02 day / kg to about 0.08 day / kg per month during the induction cycle.

[0183] In another embodiment, the present invention provides the use of cladribine according to the present invention whereby the pharmaceutical formulation is orally administered from about 0.02 day / kg to about 0.08 day / kg per month during a maintenance period.

[0184] In another embodiment, the present invention provides the use of cladribine according to the present invention, wherein the pharmaceutical formulation is to be orally administered at a daily dose of about 10 mg cladribine from day 1 to about day 2 of each month during the induction cycle.

[0185] In another embodiment, the present invention provides the use of cladribine according to the present invention, wherein the pharmaceutical formulation is to be orally administered at a daily dose of about 10 mg cladribine from day 1 to about day 3 of each month during the induction cycle.

[0186] In another embodiment, the present invention provides the use of cladribine according to the present invention, wherein the pharmaceutical formulation is to be orally administered at a daily dose of about 10 mg cladribine from day 1 to about day 4 of each month during the induction cycle.

[0187] In another embodiment, the present invention provides the use of cladribine according to the present invention, wherein the pharmaceutical formulation is to be orally administered at a daily dose of about 10 mg cladribine from day 1 to about day 5 of each month during the induction cycle.

[0188] In another embodiment, the present invention provides the use of cladribine according to the present invention, wherein the pharmaceutical formulation is to be orally administered at a daily dose of about 10 mg cladribine from day 1 to about day 6 of each month during the induction cycle.

[0189] In another embodiment, the invention provides the use of cladribine according to the invention, wherein the pharmaceutical formulation is to be administered orally from day 1 to about day 4 of each month at a daily dose of about 10 mg cladribine during the induction cycle, and wherein the pharmaceutical formulation is a pharmaceutical formulation as described in WO 2004 / 087101 or in WO 2004 / 087100.

[0190] In another embodiment, the invention provides the use of cladribine according to any of the preceding sections, wherein the pharmaceutical formulation is to be administered in combination with interferon-β.

[0191] In a preferred embodiment, the present invention provides a method for treating progressive forms of multiple sclerosis, preferably PPMS and / or SPMS, comprising orally administering cladribine or a pharmaceutical formulation thereof to a patient in need thereof, comprising the following steps: (i) an induction period, preferably an induction period of about 2 months, wherein cladribine or a pharmaceutical formulation thereof is administered, and wherein the total dose of cladribine achieved at the end of the induction period is from about 1.5 mg / kg to about 3.5 mg / kg, preferably about 1.75 mg / kg or about 3.5 mg / kg, more preferably about 1.75 mg / kg; (ii) a cladribine-free cycle, preferably a cladribine-free cycle of at least 10 months, in which cladribine is not administered; (iii) a maintenance period, preferably a maintenance period of about 2 months, wherein cladribine or a pharmaceutical formulation thereof is administered, and wherein the total dose of cladribine achieved at the end of the maintenance period is lower than or equal to the total dose of cladribine achieved at the end of the induction period (i), preferably about 1.75 mg / kg or about 3.5 mg / kg, more preferably about 1.75 mg / kg; (iv) a cladribine-free cycle, preferably a cladribine-free cycle of at least 10 months, wherein cladribine is not administered.

[0192] In a preferred embodiment, the present invention provides a method for treating progressive forms of multiple sclerosis, preferably PPMS and / or SPMS, comprising orally administering cladribine or a pharmaceutical formulation thereof to a patient in need thereof, comprising the following steps: (i) an induction cycle, wherein cladribine or a pharmaceutical formulation thereof is administered, and wherein the total effective dose of cladribine achieved at the end of the induction cycle is from about 0.7 mg / kg to about 1.4 mg / kg; (ii) no cladribine cycle, in which cladribine was not administered; (iii) a maintenance cycle, wherein the cladribine pharmaceutical formulation is administered, and wherein the total effective dose of cladribine achieved at the end of the maintenance cycle is less than or equal to the total effective dose of cladribine achieved at the end of the induction cycle (i); (iv) Cladribine-free cycles, in which no cladribine is administered.

[0193] In yet another embodiment, the present invention provides a method according to the present invention, wherein steps (iii) to (iv) are repeated at least once or twice.

[0194] In this aspect, the cladribine-free period (iv) preferably lasts at least about 24 months, or at least about 18 months, or at least 12 months, or at least about 10 months, or at least about 9 months, or at least about 8 months.

[0195] In a preferred embodiment, the present invention provides a method of using cladribine to treat progressive forms of multiple sclerosis, preferably PPMS and / or SPMS, wherein cladribine is orally administered according to the following consecutive steps: (i) administering cladribine such that the total cladribine dose achieved at the end of the induction period is about 1.7 mg / kg to about 3.5 mg / kg, preferably about 1.75 mg / kg or about 3.5 mg / kg, more preferably 1.75 mg / kg; (ii) no cladribine administration during cladribine-free cycles; (iii) administering cladribine such that the total dose of cladribine achieved at the end of the maintenance period is less than or equal to the total dose of cladribine achieved at the end of the induction period (i), preferably about 1.75 mg / kg or about 3.5 mg / kg, more preferably about 1.75 mg / kg; (iv) and optionally, a cladribine-free cycle, wherein cladribine is not administered.

[0196] In another preferred embodiment, the present invention provides a method wherein the induction period lasts up to about 4 months, or up to about 3 months, or up to about 2 months.

[0197] In another preferred embodiment, the present invention provides a method wherein the total dose of cladribine achieved at the end of the induction period is about 1.75 mg / kg.

[0198] In another preferred embodiment, the present invention provides a method wherein the total dose of cladribine achieved at the end of the induction period is about 3.5 mg / kg.

[0199] In another preferred embodiment, the present invention provides a method wherein the total effective dose of cladribine achieved at the end of the induction period is about 1.4 mg / kg.

[0200] In another preferred embodiment, the invention provides a method wherein the cladribine-free period lasts up to about 18 months, or up to 12 months, or up to 10 months, or up to about 9 months, or up to about 8 months.

[0201] In another preferred embodiment, the present invention provides a method, wherein the cladribine-free period (ii) lasts up to about 18 months, or up to 12 months, or up to 10 months, or up to about 9 months, or up to about 8 months.

[0202] In another preferred embodiment, the present invention provides a method wherein the maintenance period lasts up to about 4 months, or up to about 3 months, or up to about 2 months.

[0203] In another preferred embodiment, the present invention provides a method wherein the total dose of cladribine achieved at the end of the maintenance period is about 1.75 mg / kg.

[0204] In another preferred embodiment, the present invention provides a method wherein the total effective dose of cladribine achieved at the end of the maintenance period is about 0.7 mg / kg.

[0205] In another preferred embodiment, the present invention provides a method wherein the maintenance period is followed by a cladribine-free period.

[0206] In yet another embodiment, the invention provides a method according to the invention, wherein the total dose of cladribine achieved at the end of the induction period is about 3.5 mg / kg and the total dose of cladribine achieved at the end of the maintenance period is about 1.75 mg / kg.

[0207] In another other embodiment, the present invention provides a method according to the present invention, wherein the total effective dose of cladribine achieved at the end of the induction period is about 1.4 mg / kg and the total effective dose of cladribine achieved at the end of the maintenance period is about 0.7 mg / kg.

[0208] In yet another embodiment, the present invention provides a method according to the present invention, wherein Cladribine will be administered orally in a daily dose of about 3 to about 30 mg.

[0209] In yet another embodiment, the present invention provides a method according to the present invention, wherein Cladribine will be administered orally in a daily dose of about 10 mg.

[0210] In yet another embodiment, the present invention provides a method according to the present invention, wherein cladribine is orally administered from about 1 day to about 7 days per month during the induction cycle.

[0211] In yet another embodiment, the present invention provides a method according to the present invention, wherein step (iii) is repeated at least once or twice.

[0212] In another further embodiment, the present invention provides a method according to the present invention, wherein Cladribine is administered in combination with interferon-β.

[0213] In the following further particularly preferred aspects of cladribine for use as described and / or claimed herein are described, preferably cladribine tablets for use as described and / or claimed herein, their properties and / or their use: Preferred medicinal products Cladribine 10 mg tablet Qualitative and quantitative composition: Each tablet contains 10 mg of cladribine Excipients with known effect: Each tablet contains 64 mg sorbitol Preferred drug forms: Tablets; White round biconvex tablets with a diameter of 8.5 mm Preferred clinical details: Posology and method of administration Dosimetry The recommended cumulative dose of cladribine tablets is 3.5 mg / kg body weight over 2 years, administered as 1 course of 1.75 mg / kg per year. Each course consists of 2 treatment weeks, one at the beginning of the first month of each treatment year and one at the beginning of the second month of each treatment year. Each treatment week consists of 4 or 5 days, on which days the patient receives 10 mg or 20 mg (one or two tablets) as a single daily dose depending on body weight. For details, see Tables 1 and 2 below.

[0214] Criteria for initiating and continuing treatment Lymphocyte count is recommended Normal in year 1 before starting MAVENCLAD, At least 800 cells / mm before starting MAVENCLAD in year 2 3 .

[0215] If necessary, treatment in the second year may be delayed, preferably by up to 6 months, to allow for lymphocyte recovery.

[0216] Dose distribution The preferred distribution of total dose over 2 years of treatment is provided below in Table 1. For some weight ranges, the number of tablets may vary from one treatment week to the next.

[0217] Table 1. MAVENCLAD dose per treatment week by patient weight, per treatment year

[0218] Table 2 below shows how the total number of tablets per treatment week is distributed over the days. It is recommended that the daily dose of cladribine for each treatment week should be taken at approximately the same time each day at 24-hour intervals. If the daily dose consists of two tablets, the two tablets are taken together as a single dose.

[0219] Table 2. MAVENCLAD 10 mg tablets per weekday Total number of tablets per week Day 1 Day 2 Day 3 Day 4 Day 5 4 1 1 1 1 0 5 1 1 1 1 1 6 2 1 1 1 1 7 2 2 1 1 1 8 2 2 2 1 1 9 2 2 2 2 1 10 2 2 2 2 2 .

[0220] The missed dose must be taken as soon as you remember on the same day according to the treatment schedule.

[0221] A missed dose does not have to be taken with the next scheduled dose on the following day. In the case of a missed dose, the patient must take the missed dose on the following day and the number of days in that treatment week is extended. If two consecutive doses are missed, the same rules apply and the number of days in the treatment week is extended by two days.

[0222] Application method MAVENCLAD is for oral use. The tablets must be taken with water and swallowed without chewing. The tablets may be taken independently of food intake.

[0223] Blood monitoring The mode of action of cladribine is closely related to the decrease in lymphocyte counts. The effect on lymphocyte counts is dose-dependent. Although neutrophil counts, red blood cell counts, hematocrit, hemoglobin or platelet counts usually remain within normal limits, decreases in these parameters compared to baseline values ​​have been observed in clinical studies.

[0224] If cladribine is administered before or concomitantly with other substances that affect the hematological profile (see section 4.5), additive hematological adverse reactions can be expected.

[0225] The lymphocyte count should be determined at the following times: In year 1, before starting MAVENCLAD, In the second year before starting MAVENCLAD, · 2 months and 6 months after starting treatment in each treatment year. If the lymphocyte count is less than 500 cells / mm 3 , then it should be actively monitored until the value increases again.

[0226] Mechanism of action Cladribine is a nucleoside analog of deoxyadenosine. Chloro substitution in the purine ring protects cladribine from being decomposed by adenosine deaminase, thereby increasing the intracellular residence time of the cladribine prodrug. Subsequent phosphorylation of cladribine to its active triphosphate form, 2-chlorodeoxyadenosine triphosphate (Cd-ATP), is particularly effectively achieved in lymphocytes due to their constitutively high deoxycytidine kinase (DCK) and relatively low 5'-nucleotidase (5'-NTase) levels. A high ratio of DCK to 5'-NTase favors the accumulation of Cd-ATP, making lymphocytes particularly sensitive to cell death. As a result of a lower DCK / 5'-NTase ratio, other bone marrow-derived cells are less affected than lymphocytes. DCK is the rate-limiting enzyme for converting the cladribine prodrug into its active triphosphate form, causing selective depletion of dividing and non-dividing T and B cells.

[0227] The primary apoptosis-inducing mechanism of Cd-ATP has direct and indirect effects on DNA synthesis and mitochondrial function. In dividing cells, Cd-ATP interferes with DNA synthesis by inhibiting ribonucleotide reductase and competes with deoxyadenosine triphosphate for incorporation into DNA by DNA polymerase. In resting cells, cladribine causes DNA single-strand breaks, rapid nicotinamide adenine dinucleotide consumption, ATP consumption and cell death. There is evidence that cladribine can also cause direct caspase-dependent and caspase-independent apoptosis by releasing cytochrome c and apoptosis-inducing factor into the cytoplasm of non-dividing cells.

[0228] Pharmacodynamic effects Cladribine has been shown to exert long-lasting effects by preferentially targeting lymphocytes and the autoimmune processes involved in the pathophysiology of MS.

[0229] Across the studies, the greatest proportion of patients with grade 3 or 4 lymphocytopenia (<500 to 200 cells / mm 3 or <200 cells / mm 3 ) in patients, indicating the time interval between cladribine plasma concentration and maximum hematologic effect.

[0230] Through clinical studies, data using the recommended cumulative dose of 3.5 mg / kg body weight showed a gradual improvement in the median lymphocyte count returning to the normal range at week 84 from the first dose of cladribine (approximately 30 weeks after the last dose of cladribine). Lymphocyte counts in more than 75% of patients returned to the normal range at week 144 from the first dose of cladribine (approximately 90 weeks after the last dose of cladribine).

[0231] Treatment with oral cladribine resulted in a rapid decrease in circulating CD4+ and CD8+ T cells. CD8+ T cells had a less pronounced decrease and recovered more quickly than CD4+ T cells, resulting in a transiently reduced CD4 to CD8 ratio. Cladribine reduced CD19+ B cells and CD16+ / CD56+ natural killer cells, which also recovered more quickly than CD4+ T cells.

[0232] Clinical efficacy and safety Relapsing-remitting MS In a randomized, double-blind, placebo-controlled clinical study (CLARITY), the efficacy and safety of oral cladribine were evaluated in 1,326 patients with relapsing-remitting MS. The study objectives were to evaluate the efficacy of cladribine compared to placebo in reducing the annualised relapse rate (ARR) (primary endpoint), slowing the progression of disability, and reducing active lesions as measured by MRI.

[0233] Patients received placebo (n=437) or cumulative doses of cladribine at 3.5 mg / kg (n=433) or 5.25 mg / kg body weight (n=456) in 2 treatment cycles over a 96-week (2-year) study period. Patients randomized to the 3.5 mg / kg cumulative dose received the first treatment cycle at Weeks 1 and 5 of the first year and the second treatment cycle at Weeks 1 and 5 of the second year. Patients randomized to the 5.25 mg / kg cumulative dose received additional treatment at Weeks 9 and 13 of the first year. The majority of patients in the placebo (87.0%) and cladribine 3.5 mg / kg (91.9%) and 5.25 mg / kg (89.0%) treatment groups completed the full 96 weeks of the study.

[0234] Patients were required to have at least 1 relapse in the first 12 months. In the total study population, the median age was 39 years old (ranging from 18 to 65), and the ratio of women to men was approximately 2:1. The average duration of MS before study registration was 8.7 years, and the median baseline neurological disability based on the Kurtzke Expanded Disability Status Scale (EDSS) score in all treatment groups was 3.0 (ranging from 0 to 6.0). More than two-thirds of the study patients were not treated with MS disease-modifying drugs (DMD). The remaining patients were pretreated with interferon beta-1a, interferon beta-1b, glatiramer acetate or natalizumab.

[0235] Patients with relapsing-remitting MS who received cladribine 3.5 mg / kg showed statistically significant improvements in annualized relapse rate, proportion of patients free of relapse through 96 weeks, proportion of patients free of persistent disability through 96 weeks, and time to 3-month EDSS progression compared to patients who received placebo (see Table 3 below).

[0236] Table 3 Clinical results in the CLARITY study (96 weeks) *p<0.001 compared with placebo.

[0237] In addition, the cladribine 3.5 mg / kg treatment group was statistically significantly superior to placebo in the number and relative reduction of T1 Gd+ lesions, active T2 lesions, and combined unique lesions as demonstrated in brain MRI throughout the 96-week study. Compared to the placebo-treated group, patients taking cladribine had an 86% relative reduction in the mean number of T1 Gd+ lesions (adjusted mean numbers of 0.12 and 0.91 for the cladribine 3.5 mg / kg and placebo groups, respectively), a 73% relative reduction in the mean number of active T2 lesions (adjusted mean numbers of 0.38 and 1.43 for the cladribine 3.5 mg / kg and placebo groups, respectively), and a 74% relative reduction in the mean number of combined unique lesions per patient per scan (adjusted mean numbers of 0.43 and 1.72 for the cladribine 3.5 mg / kg and placebo groups, respectively) (p<0.001 in all 3 MRI results).

[0238] The result of a post hoc analysis of time to 6-month confirmed EDSS progression was a 47% reduction in the risk of disability progression with cladribine 3.5 mg / kg compared with placebo (hazard ratio = 0.53, 95% CI [0.36, 0.79], p < 0.05); the 10th percentile was reached at 245 days in the placebo group and was not reached at all during the study period in the cladribine 3.5 mg / kg group.

[0239] As shown in Table 3 above, the higher cumulative dose did not confer any clinically meaningful benefit but was associated with a higher incidence of grade ≥3 lymphocytopenia (44.9% in the 5.25 mg / kg group versus 25.6% in the 3.5 mg / kg group).

[0240] Patients who have completed the CLARITY study can enter the CLARITY extension. In this extension study, 806 patients received placebo or a cumulative dose of cladribine of 3.5 mg / kg (in a therapy similar to the therapy used for CLARITY) over a 96-week study period. The primary objective of the study was safety, while the efficacy endpoints were exploratory.

[0241] The magnitude of the effect in reducing relapse frequency and slowing disability progression in patients receiving the 3.5 mg / kg dose over 2 years was maintained in Years 3 and 4 (see Section 4.2).

[0242] Efficacy in patients with high disease activity Post hoc subgroup efficacy analyses have been performed in patients with high disease activity treated with oral cladribine at the recommended cumulative dose of 3.5 mg / kg. These included: Patients with 1 relapse and at least 1 T1 Gd+ lesion or 9 or more T2 lesions in the previous year while using other DMD treatments, Patients with 2 or more relapses in the previous year, regardless of whether they are currently receiving DMD treatment.

[0243] In the analysis of the CLARITY data, a consistent treatment effect on relapse was observed, with annualized relapse rates ranging from 0.16 to 0.18 in the cladribine group and from 0.47 to 0.50 in the placebo group (p<0.0001). A greater effect was observed in the time to 6 months of sustained disability compared to the overall population, with cladribine reducing the risk of disability progression by 82% (hazard ratio = 0.18, 95% CI [0.07, 0.47]). Disability progression reached the 10th percentile between weeks 16 and 23 for placebo, whereas it was not reached during the entire study period for the cladribine group.

[0244] Secondary progressive MS with relapses Supportive studies of patients treated with cladribine as an addition to interferon-β vs. treated with placebo + interferon-β also included a limited number of patients with secondary progressive MS (26 patients). In these patients, treatment with cladribine 3.5 mg / kg resulted in a reduction in the annual relapse rate compared to placebo (0.03 vs. 0.30, hazard ratio: 0.11, p<0.05). There was no difference in the annual relapse rate between patients with relapsing-remitting MS and patients with secondary progressive MS with relapses. An effect on disability progression could not be shown in any subgroup.

[0245] Patients with secondary progressive MS were excluded from the CLARITY study. However, a post hoc analysis of a mixed cohort (defined as an indicator of secondary progressive MS by a baseline EDSS score of ≥3.5) including CLARITY and ONWARD patients showed a similar reduction in annualized relapse rate compared with patients with an EDSS score of less than 3.

[0246] Pharmacokinetic properties Cladribine is a prodrug that must be intracellularly phosphorylated to become biologically active. The pharmacokinetics of Cladribine were studied in MS patients and patients with malignant diseases after oral and intravenous administration, and in an in vitro system.

[0247] absorb Following oral administration, cladribine is rapidly absorbed. Administration of 10 mg cladribine produced cladribine mean Cmax in the range of 22 to 29 ng / mL and corresponding mean AUC in the range of 80 to 101 ng·h / mL (arithmetic means from various studies).

[0248] When oral cladribine was administered in the fasting state, the median Tmax was 0.5 h (range 0.5 to 1.5 h). When administered with a high-fat meal, cladribine absorption was delayed (median Tmax was 1.5 h, range 1 to 3 h) and Cmax was reduced by 29% (based on geometric mean), while AUC was unchanged. The bioavailability of 10 mg oral cladribine is approximately 40%.

[0249] distributed The volume of distribution is large, indicating extensive tissue distribution and intracellular uptake. Studies have shown a mean volume of distribution of cladribine in the range of 480 to 490 L. Plasma protein binding of cladribine is 20% and is independent of plasma concentration.

[0250] The distribution of cladribine across biological membranes is facilitated by various transporters including ENT1, CNT3, and BCRP.

[0251] In vitro studies indicate that cladribine efflux is only minimally related to P-gp. Clinically relevant interactions with P-gp inhibitors are not expected. The potential consequences of P-gp induction on the bioavailability of cladribine have not been formally studied.

[0252] In vitro studies showed negligible transporter-mediated uptake of cladribine into human hepatocytes.

[0253] Cladribine has the potential to penetrate the blood-brain barrier. Small studies in cancer patients have shown a cerebrospinal fluid / plasma concentration ratio of approximately 0.25.

[0254] Cladribine and / or its phosphorylated metabolites substantially accumulate and remain in human lymphocytes. In vitro, the ratio of intracellular to extracellular accumulation has been found to be approximately 30 to 40 at 1 hour after cladribine exposure.

[0255] Biotransformation The metabolism of cladribine in MS patients was studied after administration of a single 10 mg tablet and a single 3 mg intravenous dose. After both oral and intravenous administration, the parent compound cladribine was the major component present in plasma and urine. The metabolite 2-chloroadenine was a minority metabolite in both plasma and urine, e.g., accounting for only ≤3% of plasma parent drug exposure after oral administration. Other metabolites could only be found in trace amounts in plasma and urine.

[0256] In the hepatic in vitro system, negligible metabolism of cladribine was observed (at least 90% was unchanged cladribine).

[0257] Cladribine is not a relevant substrate for cytochrome P450 enzymes and has not shown significant potential to act as an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Inhibition of these enzymes or genetic polymorphisms (e.g., CYP2D6, CYP2C9, or CYP2C19) is not expected to cause clinically significant effects on cladribine pharmacokinetics or exposure. Cladribine does not have a clinically significant induction effect on CYP1A2, CYP2B6, and CYP3A4 enzymes.

[0258] After entering the target cell, cladribine is phosphorylated to cladribine monophosphate (Cd-AMP) by DCK (and also by deoxyguanosine kinase in mitochondria). Cd-AMP is further phosphorylated to cladribine diphosphate (Cd-ADP) and cladribine triphosphate (Cd-ATP). The dephosphorylation and inactivation of Cd-AMP are catalyzed by cytoplasmic 5'-NTase. In the intracellular pharmacokinetic study of Cd-AMP and Cd-ATP in patients with chronic myeloid leukemia, the level of Cd-ATP was roughly half of the level of Cd-AMP.

[0259] The intracellular half-life of Cd-AMP is 15h. The intracellular half-life of Cd-ATP is 10h.

[0260] eliminate Based on pooled population pharmacokinetic data from various studies, the median elimination was 22.2 L / h for renal clearance and 23.4 L / h for non-renal clearance. Renal clearance exceeded the glomerular filtration rate, indicating active tubular secretion of cladribine.

[0261] The non-renal portion of cladribine elimination (roughly 50%) consists of negligible hepatic metabolism, and extensive intracellular distribution, and trapping of the active cladribine precursor (Cd-ATP) within targeted intracellular compartments (i.e., lymphocytes), and subsequent elimination of the intracellular Cd-ATP according to the life cycle and elimination pathways of these cells.

[0262] The estimated terminal half-life for a typical patient from population pharmacokinetic analysis is approximately 1 day. However, since this half-life accounts for only a small fraction of the AUC, it does not result in any drug accumulation after once-daily dosing.

[0263] Dose and time dependence Following oral administration of cladribine in a dose range of 3 to 20 mg, Cmax and AUC increased in a dose-proportional manner, indicating that absorption is not affected by rate- or volume-limited processes up to 20 mg oral doses.

[0264] No significant accumulation of cladribine concentrations in plasma was observed after repeated dosing. There was no indication that cladribine pharmacokinetics were altered in a time-dependent manner after repeated administration.

[0265] Specific populations No studies have been conducted to evaluate the pharmacokinetics of cladribine in the elderly, or in pediatric MS patients, or in subjects with renal or hepatic impairment.

[0266] Population kinetic analysis did not show any effect of age (range 18 to 65 years) or gender on the pharmacokinetics of cladribine.

[0267] Kidney damage Renal clearance of cladribine was shown to be dependent on creatinine clearance. Based on a population pharmacokinetic analysis including patients with normal renal function and patients with mild renal impairment, total clearance in patients with mild renal impairment (CLCR = 60 mL / min) is expected to be moderately reduced, resulting in a 25% increase in exposure.

[0268] Liver damage The effect of hepatic function on the elimination of cladribine is considered to be negligible.

[0269] Pharmacokinetic interactions A drug interaction study in MS patients showed that the bioavailability of 10 mg oral cladribine was not altered when co-administered with pantoprazole.

[0270] Preclinical safety data Nonclinical safety pharmacology and toxicology evaluations of cladribine in animal models relevant to the safety assessment of cladribine did not produce significant findings other than those predicted by the pharmacological mechanism of cladribine. The major target organs identified in repeated dose toxicology studies of up to 1 year duration in mice and monkeys by parenteral routes (intravenous or subcutaneous) were the lymphatic and hematopoietic systems. Following longer administration of cladribine to monkeys by the subcutaneous route (14 cycles), other target organs were the kidney (megakaryocytic renal tubular epithelial cells), adrenal glands (cortical atrophy and reduced cavitation), gastrointestinal tract (mucosal atrophy), and testes. Effects on the kidney were also seen in mice.

[0271] Mutagenicity Cladribine is incorporated into DNA chains and inhibits DNA synthesis and repair. Cladribine does not induce gene mutations in bacteria or mammalian cells, but it is clastogenic, causing chromosome damage in mammalian cells in vitro at concentrations 17 times higher than the expected clinical Cmax. In vivo chromosome breakage in mice was detected at 10 mg / kg, which was the lowest dose tested.

[0272] Carcinogenicity The carcinogenic potential of cladribine was assessed in mice using subcutaneous administration in a long-term 22-month study and by the oral route in transgenic mice in a short-term 26-week study.

[0273] - In the long-term carcinogenicity study in mice, the highest dose used was 10 mg / kg, a dose that was seen to be genotoxic in the mouse micronucleus study (equivalent to approximately 16 times the expected human exposure in terms of AUC in patients ingesting the maximum daily dose of 20 mg cladribine). No increased incidence of lymphoproliferative disorders or other tumor types (except Harderian gland tumours, primarily adenomas) was seen in mice. Harderian gland tumours are not considered to be clinically relevant because humans do not have a similar anatomy.

[0274] In a short-term carcinogenicity study in Tg rasH2 mice, no cladribine-related increase in the incidence of lymphoproliferative disorders or other tumor types was seen at any dose tested up to 30 mg / kg per day (equivalent to approximately 25 times the expected human exposure in terms of AUC in patients ingesting the maximum daily dose of 20 mg cladribine).

[0275] Cladribine was also evaluated in a study of 1-year-old monkeys by the subcutaneous route. No increased incidence of lymphoproliferative disorders and no tumors were seen in this study.

[0276] Although cladribine may have genotoxic potential, long-term data in mice and monkeys do not provide any evidence of a relevant increased carcinogenicity risk in humans.

[0277] Reproductive toxicity Although there was no effect on female fertility, reproductive function or general performance of the offspring, cladribine was shown to be embryolethal when administered to pregnant mice, and the compound was teratogenic in mice (also after treatment of males only) and rabbits. The observed embryolethal and teratogenic effects are consistent with the pharmacological mechanism of cladribine. In male mouse fertility studies, malformed fetuses with partial dysplasia of one or more appendages at the end of the humerus and / or femur were seen. The incidence of affected mouse fetuses in this study was in the same range of spontaneous incidence of amelia and phocomelia in this mouse line. However, considering the genotoxicity of cladribine, male-mediated effects associated with potential genetic alterations in differentiating spermatids cannot be excluded.

[0278] Cladribine did not affect fertility in male mice, but the observed testicular effects were a decrease in testicular weight and an increase in the number of non-motile sperm. Testicular degeneration and a reversible decrease in sperm with rapidly progressive motility were also seen in monkeys. Histologically, testicular degeneration was seen only in one male monkey in a 1-year subcutaneous toxicity study.

[0279] Medication Details: List of excipients Hydroxypropylbetadex (2-hydroxypropyl-β-cyclodextrin) Sorbitol Magnesium Stearate How to take MAVENCLAD This medicine is preferably taken exactly as recommended by your doctor. If in doubt, check with the doctor or pharmacist who recommended it.

[0280] Treatment Patients were given MAVENCLAD in two courses over 2 years.

[0281] Each treatment course consisted of 2 treatment weeks separated by one month at the beginning of each treatment year.

[0282] The treatment week consisted of 4 or 5 days of receiving 1 or 2 tablets daily (see Table 4).

[0283] Example: If treatment is started in mid-April, tablets are taken as shown in Table 4 below: Table 4

[0284] Before starting a course of treatment, your doctor will do a blood test to check that the level of lymphocytes (a type of white blood cell) is within an acceptable range. If this is not the case, treatment may be delayed.

[0285] Once the patient has completed 2 courses of treatment over 2 years, the physician will preferably continue to monitor the health status of each patient for an additional 2 years, wherein each subject preferably does not need to take medication.

[0286] dose 1. Based on body weight, each patient will be prescribed the correct number of tablets for each treatment week, as shown directly below in Table 2.

[0287] 2. Each patient will receive one or more packages of Cladribine tablets to provide the correct number of tablets.

[0288] 3. After receiving each supply of medication by each patient, it is recommended that each patient verify that he or she has received the correct number of tablets.

[0289] 4. In the left column of Table 5 below, each patient can preferably find the row that is appropriate to his or her body weight in kg and should then check again the number of tablets that should be in the pack for the treatment week that he or she will start.

[0290] 5. If the number of tablets in each pack differs from the number shown in Table 5 for each patient of each body weight, the doctor should be contacted.

[0291] 6. It is important to note that for some weight ranges, the number of tablets may vary from one treatment week to the next.

[0292] Example: If each patient weighs 85 kg and is about to start Week 1 of treatment, he or she will be given 8 tablets.

[0293] How to take the medicine One or more tablets will be taken at about the same time each day and swallowed without chewing. It is not required to take the tablets with meals, the tablets may be taken with or between meals.

[0294] Table 5

[0295] Duration of treatment week Depending on the total number of tablets prescribed, they must be taken over 4 or 5 days in each treatment week.

[0296] Table 6 below shows how many tablets (1 or 2 tablets) must be taken daily. If the daily dose is 2 tablets, they are preferably taken at the same time.

[0297] Example: If 8 tablets must be taken, take 2 tablets on day 1, 2, 3, then 1 tablet on day 4 and 5.

[0298] Table 6 Total number of tablets per treatment week Day 1 Day 2 Day 3 Day 4 Day 5 4 1 1 1 1 0 5 1 1 1 1 1 6 2 1 1 1 1 7 2 2 1 1 1 8 2 2 2 1 1 9 2 2 2 2 1 10 2 2 2 2 2 .

[0299] Other Information The following abbreviations preferably refer to the following definitions, respectively: kg (kilogram), μg (microgram), mg (milligram), AE (adverse effect), CNS (central nervous system), CSF (cerebrospinal fluid), EDSS (expanded disability status scale), SNRS (Scripps Neurological Rating Scale), IFN (interferon), iv (intravenous), MIU (million international units), MS (multiple sclerosis), MRI (magnetic resonance imaging), po (oral), PPMS (primary progressive multiple sclerosis), PRMS (progressive relapsing multiple sclerosis), RRMS (relapsing-remitting multiple sclerosis), SPMS (secondary progressive multiple sclerosis), sc (subcutaneous), TIW (three times a week), 2-CdA (2-chloro-2′-deoxyadenosine or cladribine), UI (international unit).

[0300] As used herein with respect to numbers, figures, ranges and / or amounts, the term "about" is preferably intended to mean "around" and / or "approximately". The meanings of those terms are well known in the art, and preferably include differences, deviations and / or variations of plus / minus 15%, and especially plus / minus 10% for the respective numbers, figures, ranges and / or amounts.

[0301] In any case, as used herein with respect to numbers, figures, ranges and / or amounts, the term "about" is preferably intended to mean "around" and / or "approximately". The meanings of those terms are well known in the art, and preferably include differences, deviations and / or variations of at least plus / minus 5% for the respective numbers, figures, ranges and / or amounts.

[0302] The terms "disorder(s)" and "disease(s)" used as described herein are well known and understood in the art. In the context of the present invention, if there is no strong suggestion in the context in which these terms are used herein, these terms are preferably used as synonyms and are thus preferably interchangeable.

[0303] In the medical context including, but not limited to, therapeutic regimens, dosing schedules, and clinical trial designs, the terms "week / a week", "month / a month", and / or "year / a year" may be used with slight deviations from the definition of the Gregorian calendar for the convenience and / or ease of use of patients, medical staff, and / or physicians, as well as reliability and / or reproducibility of results, etc. For example, in such medical contexts, a month typically refers to 28 days, and a year typically refers to 48 weeks.

[0304] Thus, in the context of the present invention, the term "week" or "a week" preferably refers to a time period of about 5 days, about 6 days or about 7 days, more preferably about 7 days.

[0305] In the medical context, the term "month" or "a month" preferably refers to a time period of about 28 days, about 29 days, about 30 days or about 31 days, more preferably about 28 days, about 30 days or about 31 days.

[0306] In the medical context, the term "year" or "a year" preferably refers to a time period of about 12 months, or about 48 weeks, about 50 weeks or about 52 weeks, more preferably 12 months, or about 48 weeks or about 52 weeks.

[0307] Particularly preferred according to the invention are themes as described herein, wherein the features of two or more than two preferred, more preferred and / or particularly preferred embodiments, aspects and / or themes are combined into one embodiment, aspect and / or theme. Preferably, according to the invention, preferred themes or embodiments can be combined with other preferred themes or embodiments; more preferred themes or embodiments can be combined with other less preferred or even more preferred themes or embodiments; particularly preferred themes or embodiments can be combined with other just preferred or just even more preferred themes or embodiments, etc.

[0308] The invention is explained in more detail below by way of examples. The invention can preferably be implemented throughout the scope of the claims and is not restricted to the examples given here.

[0309] In addition, the following examples are given to help those skilled in the art better understand the present invention by way of illustration. The examples are not intended to limit the scope of protection conferred by the claims. The features, characteristics and advantages illustrated for the methods, compounds, compositions and / or uses defined in the examples may be attributed to other methods, compounds, compositions and / or uses that are not specifically described and / or defined in the examples but fall within the scope defined in the claims.

[0310] Therefore, the following examples describe the present invention in more detail but do not limit the scope of the present invention and its claimed scope. Example

[0311] Example 1: ONWARD Study design Patients aged 18-65 years were eligible to enter the ONWARD study if they met the following criteria: - Diagnosis of relapsing RRMS or SPMS (2005 McDonald criteria)4 - Treated with IFN-β for ≥48 consecutive weeks prior to screening, with ≥1 MS relapse during that period - Clinical stability (except for relapse) during the 28 days prior to screening - Expanded Disability Status Scale (EDSS) score of 1.0-5.5 - Normal hematologic parameters within 28 days of baseline (randomization day 1), defined as: platelets, 140-450 × 103 / μL; absolute neutrophil count, 2.03-8.36 × 103 / μL; absolute lymphocyte count, 1.02-3.36 × 103 / μL; white blood cell count, 4.1-12.3 × 103 / μL; hemoglobin, 11.6-16.2 g / dL If patients were on stable therapy with current IFN-β for ≥3 months before screening, switching from one IFN-β treatment to another was allowed within 48 weeks before screening; Patients were excluded if they had infectious or immunocompromising diseases, had been previously treated with immunosuppressive or cytotoxic therapy, or if they were pregnant, breastfeeding, or refused to use contraception during the study; In the study, cladribine tablets at a dose of 3.5 mg / kg will be used as an add-on to existing IFN-β therapy; All analyses were post hoc and not pre-specified, and the resulting p-values ​​were not adjusted for multiplicity. All comparisons with p-values ​​less than 0.05 by statistical tests should be considered nominally significant.

[0312] See Figure 1 ONWARD study design introduce In the CLARITY study, cladribine tablets given annually for 2 years in short courses to patients with relapsing-remitting multiple sclerosis (RRMS) significantly improved clinical and MRI outcomes. In the 2-year CLARITY extension study, the initial 2 years of clinical benefit of cladribine treatment (3.5 mg / kg body weight) given in CLARITY was shown to be durable in patients re-randomized to receive placebo in the absence of other effective treatments. The ONWARD study confirmed the safety and tolerability of cladribine tablets (3.5 mg / kg) administered as an add-on to interferon-β (IFN-β) therapy as a primary endpoint in patients who experienced at least one relapse while receiving IFN-β. The ONWARD study also confirmed efficacy as a secondary objective and showed similar benefit of cladribine tablets 3.5 mg / kg added to IFN-β in patients with relapsing MS (RMS). However, the ONWARD study enrolled patients with RMS (described below) Figure 1 ), where patients were eligible to enter the study if they had RRMS or had relapsing secondary progressive MS (SPMS). Including patients with SPMS in ONWARD provided the opportunity to confirm the therapeutic efficacy of cladribine tablets 3.5 mg / kg added to IFN-β compared to placebo in these patients. The initial objective was to confirm the effect of cladribine tablets 3.5 mg / kg in patients with SPMS or RRMS in the ONWARD study.

[0313] EDSS, expanded disability status scale; Gd+, gadolinium-enhanced; RRMS, relapsing-remitting multiple sclerosis; −SD, standard deviation; SPMS, secondary progressive multiple sclerosis. a Overall N for placebo and 3.5 mg / kg cladribine groups, excluding 5.25 mg / kg cladribine group in ITT population (patients randomized according to both original and amended protocols) Clinical Efficacy In patients with SPMS and in patients with RRMS, patients treated with cladribine tablets 3.5 mg / kg showed a nominal statistically significant reduction in the annual relapse rate compared to placebo. In SPMS patients, the annual relapse rate was 0.03 (95% CI: 0.00-0.24) for patients treated with cladribine 3.5 mg / kg + IFN-β and 0.30 (95% CI 0.13-0.73) for those receiving placebo + IFN-β. SPMS patients treated with cladribine were 89% less likely to have a qualifying relapse than those treated with placebo ( Figure 2 ).

[0314] See also Figure 2 : Qualified relapse rate (annualized, adjusted) in patients with SPMS treated with cladribine tablets 3.5 mg / kg + IFN-β or placebo + IFN-β in ONWARD (89% risk reduction for SPMS patients treated with cladribine compared with placebo) In contrast, in RRMS patients, the annual relapse rate was 0.15 (95% CI: 0.11-0.22) for patients treated with cladribine 3.5 mg / kg + IFN-β and 0.31 (95% CI 0.21-0.45) for those receiving placebo + IFN-β. Thus, RRMS patients treated with cladribine were only 50% less likely to have a qualifying relapse than those treated with placebo ( Figure 3 ).

[0315] See also Figure 3 Qualified relapse rate (annualized, adjusted) in patients with RRMS treated with cladribine tablets 3.5 mg / kg + IFN-β or placebo + IFN-β in ONWARD (50% risk reduction for RRMS patients treated with cladribine compared with placebo) Disability progression No treatment effect was observed for the SPMS or RRMS subgroups in terms of time to 3-month or 6-month confirmed EDSS progression (not shown). These findings are similar to those in the overall ONWARD study population and may reflect the low number of patients in the study.

[0316] Magnetic resonance imaging (MRI) results In patients with both SPMS and RRMS, treatment with cladribine tablets 3.5 mg / kg was associated with a decrease in the mean number of T1 Gd+ lesions and the mean number of active T2 lesions (Table 2 below) Gd+, gadolinium-enhanced; RRMS, relapsing-remitting multiple sclerosis; −SD, standard deviation; SPMS, secondary progressive multiple sclerosis; a Overall N for the placebo and 3.5 mg / kg cladribine groups, excluding the 5.25 mg / kg cladribine group in the ITT population (patients randomized according to both the original and amended protocols).

[0317] Example 2: PPMS study Main Objectives To determine the efficacy of cladribine in delaying 6-month confirmed progression of disability in subjects with primary progressive multiple sclerosis (PPMS) compared with placebo.

[0318] Secondary Objectives Key Secondary Objectives: To confirm the efficacy of cladribine compared with placebo on other measures of disability progression in subjects with PPMS; • To confirm the efficacy of cladribine compared with placebo on magnetic resonance imaging (MRI) measures of disease progression in subjects with PPMS.

[0319] Security goals: To determine the safety and tolerability of treatment with oral cladribine compared with placebo in subjects with PPMS.

[0320] Methodology: It was a randomized, double-blind, two-arm, parallel-group, placebo-controlled, multicenter study to confirm the efficacy and safety of oral cladribine versus placebo in subjects with PPMS.

[0321] The study consisted of a screening period, followed by a 2-year double-blind treatment period with visits at months 0, 1, 3, 6, 9, 11, 12, 13, 15, 18, 21, and 24, followed by a 12-month safety follow-up period.

[0322] Subjects were randomized to treatment in a 1:1 ratio. Subjects receiving cladribine were given up to the recommended cumulative dose of 3.5 mg / kg body weight over 2 years (depending on meeting retreatment criteria: subjects should have a Common Terminology Criteria for Adverse Events [CTCAE] grade 0 or 1 lymphocyte count on the second year of treatment), administered as 1 cycle of 1.75 mg / kg per year.

[0323] Subjects receiving matching placebo were given their tablets on a schedule similar to that of cladribine-treated subjects.

[0324] Disability assessments including the Expanded Disability Status Scale, Timed 25-Foot Walk, and 9-hole Peg Test will be performed throughout the treatment period. Magnetic resonance imaging will also be performed. Adverse events are monitored to assess safety. In addition, patient-reported outcomes and clinician-reported outcomes are frequently assessed.

[0325] Primary endpoint: time to 6-month confirmed disability progression based on EDSS.

[0326] Key secondary endpoints: Key secondary endpoints of the study include: Time to 3-month confirmed progression of disability based on a combined score defined by: o 3-month confirmed EDSS progression and / or; o 3-month confirmed worsening (>20%) from baseline in the Timed 25-Foot Walk (T25FW) and / or; o 3-month confirmed worsening (>20%) compared to baseline in the 9-Hole Peg Test (9-HPT); Percent change from baseline in total lesion volume on T2-weighted images to month 24; · Percent change in brain volume from 6 to 24 months.

[0327] Safety endpoints: The incidence of treatment-emergent adverse events (non-serious adverse events [AEs], serious adverse events [SAEs], and adverse events of special interest [AESIs]) in subjects receiving cladribine compared with placebo; • Assessment of laboratory parameters (hematology and clinical chemistry) in subjects receiving cladribine compared to placebo.

[0328] Diagnosis and key inclusion and exclusion criteria: Inclusion criteria Male and female subjects aged 18 to 51 years (inclusive); · A diagnosis of PPMS according to the revised McDonald criteria, preferably the McDonald 2010 criteria (Polman, 2011) and confirmed by the PPMS Adjudication Committee (PPMS AC); EDSS score of 2.5 to 5.5 (inclusive); subjects with an EDSS score of 2.0 are eligible if the documented deficit affects the pyramidal or cerebellar functional systems; • Time to onset of PPMS symptoms <15 years for subjects with an EDSS score of 5.5 at screening, or <10 years for subjects with an EDSS score of 5.0 or less at screening.

[0329] Pharmaceutical Products: Dosage / Mode of Administration / Dosing Schedule: Cladribine tablets (10 mg) or matching placebo: 3.5 mg / kg body weight administered over 2 years (i.e., 1 course of 1.75 mg / kg per year), followed by an additional 12 months of observation for safety. Each course consisted of 2 treatment weeks, 1 week at the beginning of the first month of each year and 1 week at the beginning of the second month of each year. Each treatment week consisted of 4 or 5 days, in which subjects received 10 mg or 20 mg (or 1 or 2 tablets) as a single daily dose depending on body weight.

[0330] Duration of study and treatment per subject: Subjects will undergo a screening assessment followed by a 2-year treatment cycle and will then be followed for safety for an additional 12 months.

[0331] Background Information Cladribine (2-chloro-2'-deoxyadenosine, 2-CdA) is a synthetic chlorinated nucleoside analog of the naturally occurring nucleoside deoxyadenosine (Beutler, 1992) that, after intracellular activation to its triphosphate form, has been shown to act by selectively depleting T cells and B cells. The intracellular metabolism of cladribine plays an important role in the overall efficacy and safety of cladribine and is likely to be the most important non-renal elimination pathway of cladribine. Cladribine is distributed almost equally between plasma and whole blood cells and is able to penetrate the blood-brain barrier at 25% (Liliemark, 1992; Kearns, 1994).

[0332] Cladribine has a short half-life and prolonged pharmacodynamic (PD) effects on specific immune cells; most notably, reversible reductions in T-cell and B-cell counts. The gradual recovery of lymphocyte counts occurs without triggering homeostatic expansion of the remaining lymphocyte subtypes, which is potentially associated with rebound activity or autoimmunity seen with some other disease-modifying drugs (DMDs) used in MS (Jones, 2013; Zwang, 2014; Willis, 2015). This pharmacokinetic (PK) / PD profile produces a unique posology for oral drugs in the field of MS, with short courses of treatment (up to 20 days of treatment total) administered at the beginning of the first and second years.

[0333] The preferred cumulative dose of cladribine is 3.5 mg / kg body weight over 2 years (as approved for relapsing remitting MS (RMS) indications), preferably administered as 2 courses (i.e., 1.75 mg / kg per year). After completion of 2 courses, additional cladribine treatment in the 3rd and / or 4th year is not currently considered necessary but may be considered an option in PPMS and / or SPMS.

[0334] Cladribine has shown proven efficacy in relapsing MS (RMS). This clinical study is part of an overall development strategy for oral cladribine to expand the nominal indication to include not only subjects with relapsing MS, but also subjects with PPMS, due to the high and unmet medical need in this indication. Although PPMS accounts for only 10% to 15% of MS cases (Miller, 2007), the lack of widely available proven effective oral treatments highlights the unmet medical need.

[0335] Results from Phase II / III oral cladribine studies provide clinical efficacy data both individually and in integrated analyses, showing that oral cladribine is highly effective in subjects with active disease across the RMS clinical spectrum. The CLARITY study demonstrated robust clinical and MRI efficacy in a population that included both untreated and treatment-experienced RRMS. Analyses of CLARITY and CLARITY EXT showed the efficacy of cladribine in reducing relapses and slowing EDSS progression, and maintained for at least an additional 2 years after discontinuation of therapy after 2 short courses of the recommended dose of 3.5 mg / kg. The ORACLE MS study showed consistent clinical and MRI efficacy, with cladribine reducing the conversion of clinically isolated syndrome (CIS) subjects to clinically definite MS and McDonald 2005MS. ONWARD was not fully designed for formal demonstration of efficacy, but was designed for evaluation of the safety and efficacy profile of cladribine as an add-on therapy to interferon (IFN)-β; however, efficacy data do support the findings of the CLARITY study in the RMS patient population. For all of the above studies, the 5.25 mg / kg cladribine dose (and in the case of some additional studies, the 2 higher doses: 7.0 mg / kg and 8.75 mg / kg) did not add any clinically meaningful benefit compared to the 3.5 mg / kg dose. The significant efficacy of cladribine on the MRI endpoints highlights the anti-inflammatory properties of cladribine.

[0336] Selective depletion of lymphocytes, including B cells, is thought to play an important role in early PPMS. Ocrelizumab, a humanized monoclonal antibody targeting the CD20 surface molecule on B cells that triggers its depletion, has recently been approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with RRMS and early PPMS; approval was denied in Europe. No other agents are currently available for clinical use in early PPMS.

[0337] Several lines of evidence suggest that B cells and B cell-derived products may play a role in the chronic progression of MS (Fereidan-Esfahani, 2015). In RRMS and secondary progressive MS (SPMS), and in most patients with PPMS, clonally expanded B cells sequestered within the central nervous system (CNS) compartment generate oligoclonal bands and further clonally expand within lesions. Recent findings suggest that meningeal B cell infiltrates, perhaps organized in B cell follicle-like structures, may be a niche that maintains pathogenic CNS B cell function (Magliozzi, 2007). In progressive forms of MS, meningeal and perivascular B cell accumulations are often colocalized with activated T cells and macrophages, and experimental evidence suggests that these meningeal immune cell aggregates are associated with cortical lesion formation, demyelination, and microglial activation. Cladribine is a good candidate drug for PPMS due to its high efficacy demonstrated in subjects with RMS and CIS, and its ability to selectively target B cells and T cells in both the periphery and potentially the CNS, because cladribine was found to be a blood-brain barrier penetrant and enters the brain independently of vascular leakage. In addition, previous data with parenteral cladribine in chronic MS showed a trend in MRI efficacy (T1-weighted gadolinium-enhanced [T1 Gd+]) (Rice, 2000; see Section 5.2 for details). Therefore, the sponsor has designed this clinical study to confirm the effect of cladribine in subjects with PPMS. The data from this study are used to achieve an indication expansion of cladribine for patients with PPMS.

[0338] See also Figure 4 Schematic diagram of the study design for the PPMS study Table 3: Comparison of key entry criteria, baseline characteristics, and outcomes in large PPMS studies CDP = confirmed EDSS progression, CSF = cerebrospinal fluid, EDSS = expanded disability status scale, HR = hazard ratio, PPMS = primary progressive multiple sclerosis, T1 Gd+ = T1-weighted gadolinium-enhanced. For ORATORIO: Proportion of subjects with CDP at Month 12 derived from KM (Montalban, 2017). Sources: (PROMISE) Wolinsky, 2007, (OLYMPUS) Hawker, 2009, (INFORMS) Lublin, 2016, (ORATORIO) Montalban, 2017.

[0339] Based on our experience, we believe that younger PPMS populations with greater MRI activity may be more amenable to treatment, especially those with a high inflammatory burden and thus a high unmet medical need.

[0340] In summary, based on our assessment, by including a study population with PPMS aged <55 years and with lower EDSS, the opportunity to include subjects with inflammatory diseases is increased. There is an unmet need for drugs that target PPMS early before irreversible disability develops. The penetration of cladribine into the CNS (Liliemark, 1997) and its hypothesized action beyond the blood-brain barrier provide a strong further rationale for this study, as the pathophysiology of progressive forms of MS is thought to involve inflammation within the CNS.

[0341] Dosage and Administration Randomized subjects were administered oral cladribine or matching placebo in 2 annual courses during the treatment period in a blinded manner.

[0342] The first dose was administered on site and the subsequent 3-4 days of treatment were performed by the patient at home.

[0343] The recommended cumulative dose of cladribine is 3.5 mg / kg body weight over 2 years, administered as 1 course of 1.75 mg / kg per year. Each course consists of 2 treatment weeks, 1 week at the beginning of the first month (baseline) and 1 week at the beginning of the second month (month 1), and then in the second year at the beginning of months 12 and 13. Depending on body weight, each treatment week consists of 4 or 5 days, and subjects receive 10 mg or 20 mg (1 or 2 tablets) as a single daily dose on these days.

[0344] After completing 2 courses of treatment, further cladribine treatment is currently considered unnecessary in years 3 and / or 4. However, reinitiation of therapy in year 3 may be an option to further improve the patient's condition, especially in patients with PPMS.

[0345] Preferred criteria for initiating and continuing therapy The lymphocyte count must be: Normal before starting cladribine in year 1, At least Grade 0 or 1 ALC before starting cladribine in Year 2.

[0346] If necessary, treatment in the second year may be delayed for up to 6 months to allow lymphocyte recovery. If this recovery takes longer than 6 months, the patient should no longer receive cladribine.

[0347] Subjects were instructed to take the medication at the same time daily with water; the tablets must be swallowed whole. Since the tablets are uncoated, they must be taken immediately after removing the blister pack. There are no fasting restrictions; the tablets can be taken independent of food intake.

[0348] The missed dose must be taken as soon as you remember on the same day, according to the treatment plan.

[0349] A missed dose does not have to be taken with the next scheduled dose on the following day. In the event of a missed dose, the patient must take the missed dose on the following day and the number of days in the treatment week is extended. If two consecutive doses are missed, the same rules apply and the number of days in the treatment week is extended by two days.

[0350] Example 3 The efficacy and safety of oral cladribine administration, ultimately multiple dose administration, as described herein was also assessed, for example, according to the regimen for the treatment of relapsing forms of MS given as follows: Oral Cladribine in the Treatment of Relapsing Forms of MS Sixty patients with clinically confirmed relapsing forms of multiple sclerosis were studied. Each patient's normal liver, kidney, and bone marrow function was first examined to establish baseline values.

[0351] Patients were selected from males or females between the ages of 18 and 55 years with one or more relapses in the previous 12 months. Female patients were non-pregnant women.

[0352] Patients were randomly assigned to one of the treatment groups listed in Table 1 below: Table 1: Group 2-CdA 1 2 1.75mg / kg 3 3.5 mg / kg .

[0353] Each of the patients in Groups 2 and 3 received 3 mg or 10 mg of 2-CdA (administered 1, 2 or 3 times a day depending on the patient's weight) combined in a cyclodextrin formulation as described in Example 3 of WO 2004 / 087101. The composition of the cladribine formulation containing hydroxypropyl-β-cyclodextrin in a 3 mg or 10 mg 2-CdA tablet is listed in Table 2 below: Table 2: * As a separate process as described in WO 2004 / 087101, Cladribine was complexed with 2-hydroxypropyl-β-cyclodextrin and lyophilized.

[0354] The administration regimens of target doses of 1.75 mg / kg and 3.5 mg / kg for the induction cycle depending on the patient's weight are given in the following Tables 3 and 4, respectively. For the maintenance cycle, the examples of the administration regimens of Table 3 can be applied. Table 3: Table 4:

[0355] In Group 1 , patients received placebo for 4 months, followed by 8 months of no treatment.

[0356] In Group 2 Patients receive one month of daily oral administration of cladribine for about 5 days during a 2-CdA cyclodextrin formulation for 2 months (induction period), such that the total effective dose administered at the end of the first 2 months is close to about 0.7 mg / kg (total dose is about 1.75 mg / kg, bioavailability is about 40%); followed by 2 months of placebo; followed by 8 months of no treatment.

[0357] In Group 3 Patients received daily oral administration of cladribine for about 5 days during a 4-month period (induction period) of the 2-CdA cyclodextrin formulation, such that the total effective dose administered at the end of the first 4 months was approximately 1.4 mg / kg (total dose was about 3.5 mg / kg, bioavailability was about 40%); followed by 8 months without treatment.

[0358] Beginning at month 13, all three patient groups received treatment with the cyclodextrin formulation of cladribine at a lower dose (such as a total effective dose administered at the end of the first 2 months approaching about 0.7 mg / kg) for an additional 2 months (maintenance period), approximately 5 days a month, followed by 10 months without treatment.

[0359] Finally, beginning at month 25, all patient groups received treatment with the cyclodextrin formulation of cladribine at a lower dose (such as a total effective dose administered at the end of the first 2 months approaching about 0.7 mg / kg) for an additional 2 months (maintenance period), approximately 5 days a month, followed by greater than 10 months without treatment.

[0360] Patients were monitored by MRI scans and neurological examinations to determine if there was any progression or improvement of brain lesions associated with MS progression, as described in Miller et al., 1996, supra; Evans et al., 1997, supra; Sipe et al., 1984, supra; and Mattson, 2002, supra. All patients had baseline and MRI studies (brain or spinal cord, depending on the localization of the lesions) at month 12.

[0361] Patients were monitored for progression of disability and time to first relapse, as well as the proportion of relapse-free patients at 24 months.

[0362] Monitor patients' lymphocyte markers and monocyte counts.

[0363] Patients in groups 2 and 3 had reduced brain damage.

[0364] The data showed that 2-CdA therapy, including a series of induction treatment and maintenance treatment, was effective in reducing brain damage, and no serious adverse effects were observed.

Claims

1. Cladribine for oral treatment of patients suffering from progressive forms of multiple sclerosis, wherein said cladribine is orally administered to each patient at a fixed dose per patient, per unit of body weight and per year of treatment, wherein said fixed dose is selected from the range of 1.5 mg / kg to 4.0 mg / kg.

2. Cladribine for use according to claim 1, wherein the progressive form of multiple sclerosis comprises primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis.

3. Cladribine for use according to claim 1 or 2, wherein said Cladribine is to be orally administered to a patient who is also receiving one or more disease-modifying drugs different from Cladribine.

4. Cladribine for use according to claim 3, wherein the disease modifying drug other than Cladribine is selected from: Interferon beta-1a, interferon beta-1a (e.g., ), Interferon beta-1b, interferon beta-1b (e.g., ), Pegylated interferon beta 1a (e.g. ), Alemtuzumab (eg, ), Daclizumab (eg, ), Dimethyl fumarate (e.g. ), Fingolimod (eg, ), Glatiramer acetate (eg, ), Natalizumab (eg, ),and Teriflunomide (e.g., ).

5. A method of treating a patient diagnosed with a progressive form of multiple sclerosis, the method comprising: The patient is orally administered a cumulative dose of about 3.5 mg / kg body weight of cladribine over 2 years, with a maximum deviation of + / - 0.4 mg / kg, administered in 1 course of about 1.75 mg / kg + / - 0.2 mg / kg per year, wherein each course consists of 2 treatment weeks, one at the beginning of the first month of each treatment year and one at the beginning of the second month of each treatment year.

6. A method according to claim 5, wherein the progressive form of multiple sclerosis is selected from primary progressive multiple sclerosis and secondary progressive multiple sclerosis, the method comprising: The patient is orally administered a cumulative dose of about 3.5 mg / kg body weight of cladribine over 2 years, administered in 1 course of about 1.75 mg / kg, wherein each course consists of 2 treatment weeks, one at the beginning of the first month of each treatment year and one at the beginning of the second month of each treatment year.

7. A method of treating a patient suffering from a progressive form of multiple sclerosis, comprising orally administering to said patient tablets or capsules each containing about 10 mg of cladribine, wherein said tablets or capsules are administered during a cycle, referred to as a treatment year, comprising the following therapy: (i) a course of treatment lasting 2 months, wherein cladribine tablets or capsules are orally administered daily at a daily dose of 10 or 20 mg cladribine on 3 to up to 6 days of each month, preferably on 4 or 5 days of each month, preferably in the 1st week of each month (each treatment week); (ii) followed by a cladribine-free period lasting 10 months, preferably until the end of the first treatment year, wherein no cladribine is administered to the patient; Among them, patients with the following weights: - In the range of 40 to less than 50 kg, administer the following: 1) In the first treatment week of the course of treatment, 4 tablets or capsules (40 mg cladribine), 2) In the second treatment week of the course of treatment, 4 tablets or capsules (40 mg cladribine), - In the range of 50 to less than 60 kg, administer the following: 1) In the first treatment week of the course of treatment, 5 tablets or capsules (50 mg cladribine), respectively, 2) In the second treatment week of the course of treatment, 5 tablets or capsules (50 mg cladribine), - In the range of 60 to less than 70 kg, administer the following: 1) In the first treatment week of the course of treatment, 6 tablets or capsules (60 mg cladribine), 2) In the second treatment week of the course of treatment, 6 tablets or capsules (60 mg cladribine), - In the range of 70 to less than 80 kg, administer the following: 1) In the first treatment week of the course of treatment, 7 tablets or capsules (70 mg cladribine), 2) In the second treatment week of the course of treatment, 7 tablets or capsules (70 mg cladribine), - In the range of 80 to less than 90 kg, administer the following: 1) In the first treatment week of the course of treatment, 8 tablets or capsules (80 mg cladribine), 2) In the second treatment week of the course of treatment, 7 tablets or capsules (70 mg cladribine), - In the range of 90 to less than 100 kg, administer the following: 1) In the first treatment week of the course of treatment, 9 tablets or capsules (90 mg cladribine), 2) In the second treatment week of the course of treatment, 8 tablets or capsules (80 mg cladribine), - In the range of 100 to less than 110 kg, administer the following: 1) In the first treatment week of the course of treatment, 10 tablets or capsules (100 mg cladribine), 2) In the second treatment week of the course of treatment, 9 tablets or capsules (90 mg cladribine), - In the range of 110 kg and above, apply the following: 1) In the first treatment week of the course of treatment, 10 tablets or capsules (100 mg cladribine), 2) In the second treatment week of the course of treatment, 10 tablets or capsules (100 mg cladribine).

8. A method of treating a patient suffering from a progressive form of multiple sclerosis, comprising orally administering to said patient tablets or capsules each containing about 10 mg of cladribine, wherein said tablets or capsules are administered during a cycle called a treatment year according to a regimen comprising: (i) a first course of treatment lasting 2 months, wherein cladribine tablets or capsules are orally administered daily at a daily dose of 10 or 20 mg cladribine on 3 to up to 6 days of each month, preferably on 4 or 5 days of each month, preferably in the 1st week (treatment week) of each month; (ii) followed by a first cladribine-free period lasting 10 months, preferably until the end of the first treatment year, wherein no cladribine is administered to the patient; (iii) followed by a second course of treatment lasting 2 months, wherein cladribine tablets or capsules are orally administered daily at a daily dose of 10 or 20 mg cladribine on 3 to up to 6 days of each month, preferably on 4 or 5 days of each month, preferably in the 1st week (treatment week) of each month; and (iv) followed by a second cladribine-free period lasting 10 months, preferably until the end of the second treatment year, wherein no cladribine is administered to the patient, and Among them, patients with the following weights: - In the range of 40 to less than 50 kg, administer the following: 1) In the first treatment week of both the first and second cycles, 4 tablets or capsules (40 mg cladribine) respectively, 2) In the second treatment week of both the first and second cycles, 4 tablets or capsules (40 mg cladribine), respectively, - In the range of 50 to less than 60 kg, administer the following: 1) In the first treatment week of both the first and second cycles, 5 tablets or capsules (50 mg cladribine) respectively, 2) In the second treatment week of both the first and second cycles, 5 tablets or capsules (50 mg cladribine), respectively, - In the range of 60 to less than 70 kg, administer the following: 1) In the first treatment week of both the first and second cycles, 6 tablets or capsules (60 mg cladribine), respectively, 2) In the second treatment week of both the first and second cycles, 6 tablets or capsules (60 mg cladribine), respectively, - In the range of 70 to less than 80 kg, administer the following: 1) In the first treatment week of both the first and second cycles, 7 tablets or capsules (70 mg cladribine), respectively, 2) In the second treatment week of both the first and second cycles, 7 tablets or capsules (70 mg cladribine), respectively, - In the range of 80 to less than 90 kg, administer the following: 1) In the first treatment week of both the first and second cycles, 8 tablets or capsules (80 mg cladribine), respectively, 2) In the second treatment week of both the first and second cycles, 7 tablets or capsules (70 mg cladribine), respectively, - In the range of 90 to less than 100 kg, administer the following: 1) 9 tablets or capsules (90 mg cladribine) in the first treatment week of both cycles 1 and 2, 2) 8 tablets or capsules (80 mg cladribine) in the second treatment week of both cycles 1 and 2, - In the range of 100 to less than 110 kg, administer the following: 1) In the first treatment week of both cycles 1 and 2, 10 tablets or capsules (100 mg cladribine), 2) In the second treatment week of both cycles 1 and 2, 9 tablets or capsules (90 mg cladribine), - In the range of 110 kg and above, administer the following: 1) 10 tablets or capsules (100 mg cladribine) in the first treatment week of both the first and second treatment cycles, 2) 10 tablets or capsules (100 mg cladribine) in the second treatment week of both the first and second treatment cycles, respectively.

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