I 1111111111111111 11111 lllll lllll lllll 111111111111111 111111111111111 IIII IIII
`US0083 77903B2
`
`c12) United States Patent
`De Luca et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,377,903 B2
`*Feb.19,2013
`
`(54)
`
`CLADRIBINE REGIMEN FOR TREATING
`MULTIPLE SCLEROSIS
`
`(75)
`
`Inventors: Giampiero De Luca, Conches/Geneva
`(CH); Arnaud Ythier, Collex-Bossy
`(CH); Alain Munafo, Tartegnin (CH);
`Maria Lopez-Bresnahan, Lincoln, MA
`(US)
`
`(73)
`
`Assignee: Merck Serono SA, Coinsins, Vaud (CH)
`
`( *)
`
`Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 162 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21)
`
`Appl. No.: 12/766,173
`
`(22)
`
`Filed:
`
`Apr. 23, 2010
`
`(65)
`
`Prior Publication Data
`
`US 2010/0203017 Al
`Aug. 12, 2010
`Related U.S. Application Data
`
`(63) Continuation of application No. 11/722,018, filed as
`application No. PCT/EP2005/056954 on Dec. 20,
`2005, now Pat. No. 7,713,947.
`
`(60) Provisional application No. 60/638,669, filed on Dec.
`22, 2004.
`
`(30)
`
`Foreign Application Priority Data
`
`Dec. 22, 2004
`
`(EP) ..................................... 04106909
`
`(51)
`
`Int. Cl.
`A61K 31152
`(2006.01)
`A61K 3117076
`(2006.01)
`A61K 38121
`(2006.01)
`A61K 9/00
`(2006.01)
`(52) U.S. Cl. ......................................... 514/46; 424/85.6
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,964,848 A
`10/1990 Bloom
`5,506,214 A
`4/ 1996 Beutler
`2010/0021429 Al
`1/2010 Brentzel et al.
`
`FOREIGN PATENT DOCUMENTS
`O 626 853 Bl
`4/2000
`WO 2004/087101 A2
`10/2004
`
`EP
`WO
`
`OTHER PUBLICATIONS
`
`Beutler, E. et al. "Marrow Suppression Produced by Repeated Doses
`ofCladribine", Acta Haematol, 1994, pp. 10-15, vol. 91.
`Beutler, E. et al. "Treatment of Multiple Sclerosis and Other Autoim(cid:173)
`mune Diseases With Cladribine", Seminars in Hematology, Jan. 1,
`1996, pp. 45-52, vol. 33, No. 1, Supplement 1.
`Beutler, E. et al. "The treatment of chronic progressive multiple
`sclerosis with cladribine", Proc. Natl. Acad. Sci. USA, Feb. 1996, pp.
`1716-1720, vol. 93.
`
`Ellison, G. et al. "Oral Cladribine for Multiple Sclerosis", Neurology,
`Mar. 1997, P03.070, pp. Al74-Al75, vol. 48, No. 3, XP008047069.
`Grieb, P. et al. "Effect of Repeated Treatments with Cladribine
`(2-Chlorodeoxyadenosine) on Blood Counts in Multiple Sclerosis
`Patients", Archivum Immunologiae et Therapiae Experimentalis,
`1995, pp. 323-327, vol. 43, No. 5-6.
`"Synthesis of 2'-Deoxytubercidin,
`Kazimierczuk, Z. et al.
`2'-Deoxyadenosine, and Related 2'-Deoxynucleosides via a Novel
`Direct Stereospecific Sodium Salt Glycosylation Procedure", J Am.
`Chem. Soc., 1984, pp. 6379-6382, vol. 106, No. 21.
`Kurtzke, J. "Rating neurologic impairment in multiple sclerosis: An
`expanded disability status scale (EDSS)", Neurology, Nov. 1983, pp.
`1444-1452, vol. 33.
`Langtry, H. et al. "Cladribine: A Review of its Use in Multiple
`Sclerosis", Biodrugs, May 1998, pp. 419-433, vol. 9, No. 3.
`Lassmann, H. et al. "Heterogeneity of multiple sclerosis pathogen(cid:173)
`esis: implications for diagnosis and therapy", TRENDS in Molecular
`Medicine, Mar. 2001, pp. 115-121, vol. 7, No. 3.
`Lublin, F. et al. "Defining the clinical course of multiple sclerosis:
`Results of an international survey", Neurology, Apr. 1996, pp. 907-
`911, vol. 46.
`Lucchinetti, C. et al. "Multiple sclerosis: recent developments in
`neuropathology, pathogenesis, magnetic resonance imaging studies
`and treatment", Current Opinion in Neurology, 2001, pp. 259-269,
`vol. 14.
`Mattson, D. "Update on the diagnosis of multiple sclerosis", Expert
`Review ofNeurotherapeutics, May 2002, pp. 319-327, vol. 2, No. 3.
`McDonald, W. et al. "Recommended Diagnostic Criteria for Multiple
`Sclerosis: Guidlines from the International Panel on the Diagnosis of
`Multiple Sclerosis", Annals of Neurology, Jul. 2001, pp. 121-127,
`vol. 50, No. 1.
`Miller, R. et al. "Therapeutic advances inALS", Neurology, 1996, pp.
`S217, vol. 47, Suppl. 4.
`Noseworthy, J. et al. "Multiple Sclerosis", The New England Journal
`of Medicine, Sep. 28, 2000, pp. 938-952, vol. 343, No. 13.
`Poser, C. et al. "New Diagnostic Criteria for Multiple Sclerosis:
`Guidelines for Research Protocols", Annals of Neurology, Mar. 1983,
`pp. 227-231, vol. 13, No. 3.
`Rice, G. et al. "Cladribine and progressive MS: Clinical and MRI
`outcomes of a multicenter controlled trial", Neurology, Mar. 2000,
`pp. 1145-1155, vol. 54.
`Romine, J. et al. "A Double-Blind, Placebo-Controlled, Randomized
`Trial ofCladribine in Relapsing-Remitting Multiple Sclerosis", Pro(cid:173)
`ceedings of the Association of American Physicians, Jan./Feb. 1999,
`pp. 35-44, vol. 111, No. 1.
`Schumacher, G. et al. "Problems of Experimental Trials of Therapy in
`Multiple Sclerosis: Report by the Panel on the Evaluation of Experi(cid:173)
`mental Trials of Therapy in Multiple Sclerosis", Annals New York
`Academy of Sciences, Mar. 31, 1965, pp. 552-568, vol. 122.
`
`(Continued)
`
`Primary Examiner - Elizabeth C Kemmerer
`Assistant Examiner - Kimberly A Ballard
`(74) Attorney, Agent, or Firm - Saliwanchik, Lloyd &
`Eisenschenk
`
`(57)
`
`ABSTRACT
`The present invention is related to the use of Cladribine for the
`preparation of a pharmaceutical formulation for the treatment
`of multiple sclerosis, especially relapsing-remitting multiple
`sclerosis or early secondary progressive multiple sclerosis,
`wherein the preparation is to be the orally administered and
`wherein re-treatments are possible.
`
`29 Claims, No Drawings
`
`Hopewell EX1001
`
`1
`
`

`

`US 8,377,903 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`Selby, R. et al. "Safety and Tolerability of Subcutaneous Cladribine
`Therapy in Progressive Multiple Sclerosis", Can. J Neural. Sci.,
`1998, pp. 295-299, vol. 25.
`
`Sipe, J. et al. "A neurologic rating scale (NRS) for use in multiple
`sclerosis", Neurology, Oct. 1984, pp. 1368-1372, vol. 34.
`Stelmasiak, Z.
`et
`al.
`"A
`pilot
`trial
`cladribine
`of
`(2-chlorodeoxyadenosine) in remitting-relapsing multiple sclero(cid:173)
`sis", Med. Sci Monit., 1998, pp. 4-8, vol. 4, No. 1.
`
`2
`
`

`

`US 8,377,903 B2
`
`5
`
`1
`CLADRIBINE REGIMEN FOR TREATING
`MULTIPLE SCLEROSIS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation of U.S. Ser. No. 11/722,
`018, filed Jun. 18, 2007, which is the U.S. national stage
`application of International Patent Application No. PCT/
`EP2005/056954, filed Dec. 20, 2005, which claims the ben(cid:173)
`efit of U.S. Provisional Patent Application No. 60/638,669,
`filed Dec. 22, 2004, the disclosures of which are hereby
`incorporated by reference in their entireties, including all
`figures, tables and amino acid or nucleic acid sequences.
`
`FIELD OF THE INVENTION
`
`The present invention relates to the use of multiple doses of
`Cladribine for the treatment of multiple sclerosis, especially
`relapsing-remitting multiple sclerosis or early secondary pro(cid:173)
`gressive multiple sclerosis.
`
`BACKGROUND OF THE INVENTION
`
`2
`cations for disease classification (Lassmann et al., 2001,
`Trends Mal. Med., 7, 115-121; Lucchinetti et al., Curr. Opin.
`Neural., 2001, 14, 259-269).
`MS onset is defined by the occurrence of the first neuro-
`logical symptoms of CNS dysfunction. Advances in cere(cid:173)
`brospinal fluid (CSF) analysis and magnetic resonance imag(cid:173)
`ing (MRI) have simplified the diagnostic process and
`facilitated early diagnostic (Noseworthy et al., The New
`England Journal of Medicine, 2000, 343, 13, 938-952). The
`10 International Panel on the Diagnosis of MS issued revised
`criteria facilitating the diagnosis of MS and including MRI
`together with clinical and para-clinical diagnostic methods
`(Mc Donald et al., 2001, Ann. Neural., 50:121-127).
`Current medications for MS which are disease modifying
`15 treatments, i.e. modifying the course of MS, modulate or
`suppress the immune system. There are four FDA approved
`immunomodulating agents for RRMS: three beta interferons
`(Betaseron®, Berlex; Avonex®, Biogen; Rebif®, Serano)
`and Glatimarer Acetate (Copaxone®, Amgen). There is also
`20 one FDA approved immunosuppressing drug for worsening
`MS, Mitoxantrone (Novantrone®, Amgen). Several other
`immunosuppressive agents are used, although not FDA
`approved.
`Among them, Cladribine, a chlorinated purine analogue
`25 2-chloro-2' deoxyadenosine analogue (2-CdA), has been sug(cid:173)
`gested to be useful in the treatment of MS (EP 626853B 1 and
`U.S. Pat. No. 5,506,214).
`Several clinical studies with Cladribine in patients with
`multiple sclerosis have investigated the use of i.v. and s.c.
`30 Cladribine in MS.
`Two double-blind, placebo controlled Phase II studies
`were conducted respectively in the treatment of Chronic Pro(cid:173)
`gressive MS (Selby et al., 1998, Can. J. Neural. Sci., 25:295-
`299) and Relapsing-Remitting MS respectively (Romine et
`35 al., 1999, Proceedings of the Association of American Physi(cid:173)
`cians, 111, 1, 35-44).
`In the first trial, the Cladribine dose used was 0.1 mg/kg/
`day for 7 days by continuous i.v. infusion. The treatment for
`repeated for 4 consecutive months.
`In the second clinical trial, the Cladribine dose used was
`0.07 mg/kg/day for 5 days by subcutaneous injection. The
`treatment was repeated for 6 consecutive months.
`In addition, placebo controlled Phase III study was con(cid:173)
`ducted in patients with primary progressive (PP) or secondary
`progressive (SP) multiple sclerosis (Rice at al., 2000, Neurol(cid:173)
`ogy, 54, 5, 1145-1155). In this study, both patient groups
`received Cladribine by subcutaneous injection at a dose of
`0.07 mg/kg/day. The treatment was repeated for either 2
`months or 6 months.
`The Phase II clinical studies provided 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 Reso(cid:173)
`nance Imaging (MRI) findings (Beutler et al., 1996, Proc.
`Nat. Acad. Sci. USA, 93, 1716-1720; Romine et al., 1999
`above). Phase III study results, were positive on the signifi-
`cant reduction of MRI-measured brain lesions (Rice at al.,
`2000, above).
`Some adverse effects (AEs ), such as increased incidence of
`infections related to compromised immune function or
`myelosuppression, were observed with the highest doses
`(Selby et al., 1998, above; Beutler et al., 1994,Acta hematol.,
`91:10-15). Due to the narrow margin of safety between the
`efficacy dose and the dose of occurrence of AEs, to date, all
`clinical trials for Cladribine in multiple sclerosis have been
`conducted using either i.v. or s.c. administration. As a result,
`Beutler et al. (Beutler et al., 1996, Seminars in Hematology,
`
`Multiple sclerosis (MS) is the most known chronic inflam(cid:173)
`matory demyelinating disease of the central nervous system
`in humans. The onset of the disease typically occurs during
`ages 20 to 40. Women are affected approximately twice as
`often as men.
`Over time, MS may result in the accumulation of various
`neurological disabilities. Clinical disability in MS is pre(cid:173)
`sumed to be a result of repeated inflammatory injury with
`subsequent loss of myelin and axons, leading to tissue atro(cid:173)
`phy.
`MS is manifested in physical symptoms (relapses and dis(cid:173)
`ability progression), Central Nervous System (CNS) inflam(cid:173)
`mation, brain atrophy and cognitive impairment. Presenting
`symptoms include focal sensory deficits, focal weakness,
`visual problems, imbalance and fatigue. Sexual impairment 40
`and sphincter dysfunction may occur. Approximately half of
`the patients with MS may experience cognitive impairment or
`depression.
`MS is now considered to be a multi-phasic disease and
`periods of clinical quiescence (remissions) occur between 45
`exacerbations. Remissions vary in length and may last several
`years but are infrequently permanent.
`Four courses of the disease are individualized: relapsing(cid:173)
`remitting (RR), secondary progressive (SP), primary progres(cid:173)
`sive (PP) and progressive relapsing (PR) multiple sclerosis.
`More than 80% of patients with MS will initially display a
`RR course with clinical exacerbation of neurological symp(cid:173)
`toms, followed by a recovery that may or may not be complete
`(Lublin and Reingold, Neurology, 1996, 46:907-911).
`During RRMS, accumulation of disability results from 55
`incomplete recovery from relapses. Approximately, half of
`the patients with RRMS switch to a progressive course, called
`SPMS, 10 years after the diseased onset. During the SP phase,
`worsening of disability results from the accumulation of
`residual symptoms after exarcerbation but also from insidi- 60
`ous progression between exacerbations (Lublin and Reingold
`above). 10% of MS patients have PPMS which is character(cid:173)
`ized by insidious progression of the symptoms from the dis(cid:173)
`ease onset. Less than 5% of patients have PRMS and are often
`considered to have the same prognosis as PPMS. It is sug- 65
`gested that distinct pathogenic mechanisms may be involved
`in different patient sub-groups and have wide-ranging imp Ii-
`
`50
`
`3
`
`

`

`3
`33, l(Sl), 45-52) excluded the oral route for the treatment of
`multiple sclerosis with Cladribine.
`Grieb et al. reported a small trial in 11 patients with remit(cid:173)
`ting-relapsing multiple sclerosis (Grieb et al., 1995, Archi(cid:173)
`vum Immunologiae et Therapiae Experimentalis, 43 (5-6),
`323-327) wherein Cladribine has been orally administered
`during 6 monthly courses of 5 days at a total dose of about
`4-5.7 mg/kg (patients of about 52 and about 75 kilos, respec(cid:173)
`tively) i.e. a total effective dose of 2-2.85 mg/kg. For some
`patients, a single re-treatment of 5 days was performed at a 10
`cumulative dose of 0.4-0.66 mg/kg after a cladribine free(cid:173)
`period of 3 or 6 months. The side effects observed with the
`regimen above were said to be less severe than the ones
`observed in the study on patients suffering from chronic pro(cid:173)
`gressive multiple sclerosis treated by i.v. infusion ofCladrib- 15
`ine (Sipe et al., 1994, Lancet, 344, 9-13) but were still present.
`In addition, the therapeutic efficacy of the oral regimen above
`versus the i.v. infusion therapy was questioned (Grieb et al.,
`1995, above) and a group of"non-responders" has been iden(cid:173)
`tified (Stelmasiak et al., 1998, Laboratory Investigations, 20
`4(1), 4-8).
`Therefore, it would be desirable to have a method for
`treating multiple sclerosis comprising the oral administration
`of Cladribine that would permit the same or improved effect
`on MS lesions while decreasing the occurrence and/or sever- 25
`ity adverse events. In addition, as MS is a chronic disease, it
`would be desirable to decrease the occurrence and/or severity
`adverse events in such a way that re-treatments are possible.
`A sustained benefit ofCladribine treatment between the treat-
`ment periods is also desirable.
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed towards a use of Cladrib(cid:173)
`ine for the preparation of a pharmaceutical formulation for
`the treatment of multiple sclerosis, wherein the preparation is
`to be the orally administered. Particularly, the invention is
`directed towards a use of Cladribine for the preparation of a
`medicament for the treatment of relapsing-remitting multiple
`sclerosis or early secondary progressive multiple sclerosis
`and wherein re-treatments are possible.
`An embodiment of the invention provides an improved
`dosing regimen for Cladribine in the treatment of multiple
`sclerosis.
`An additional embodiment of the invention provides a use 45
`of Cladribine for the preparation of a pharmaceutical formu(cid:173)
`lation for the treatment of multiple sclerosis wherein adverse
`effects are reduced, allowing further use of Cladribine.
`In one embodiment, the invention provides a use of
`Cladribine for the preparation of a pharmaceutical formula(cid:173)
`tion wherein the formulation is to be orally administered
`following the sequential steps below:
`(i) An induction period wherein the Cladribine pharmaceu(cid:173)
`tical formulation is administered and wherein the total
`dose of Cladribine reached at the end of the induction 55
`period is from about 1.7 mg/kg to about 3.5 mg/kg;
`(ii) A Cladribine-free period wherein no Cladribine is
`administered;
`(iii) A maintenance period wherein Cladribine pharmaceu(cid:173)
`tical formulation is administered and wherein the total
`dose ofCladribine reached at the end of the maintenance
`period is lower than the total dose of Cladribine reached
`at the end of the induction period (i);
`(iv) A Cladribine-free period wherein no Cladribine is
`administered.
`In another embodiment, the invention provides a method
`for the treatment of multiple sclerosis, comprising the oral
`
`65
`
`US 8,377,903 B2
`
`4
`administration of Cladribine or of a formulation thereof in a
`patient in need thereof comprising the following steps:
`(i) An induction treatment wherein the total dose of
`Cladribine reached at the end of the induction period is
`from about 1.7 mg/kg to about 3.5 mg/kg;
`(ii) A Cladribine-free period wherein no Cladribine is
`administered;
`(iii) A maintenance treatment wherein the total dose of
`Cladribine reached at the end of the maintenance period
`is lower than the total dose of Cladribine reached at the
`end of the induction period (i);
`(iv) A Cladribine-free period wherein no Cladribine is
`administered.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Definitions
`
`The "total dose" or "cumulative dose" refers to the total
`dose of Cladribine administered during the treatment, i.e. the
`dose reached at the end of the treatment that is calculated by
`adding the daily doses. For example, the total dose of Cladrib(cid:173)
`ine corresponding to a treatment of0.7 mg/kg Cladribine per
`day during 5 days is 3.5 mg/kg or the total dose ofCladribine
`corresponding to a treatment of 0.35 mg/kg Cladribine per
`day during 5 days is 1.7 mg/kg.
`"The total effective dose" or "cumulative effective dose"
`refers to the bioavailable dose of Cladribine after a given
`administration period, i.e. the bioavailable dose reached at the
`30 end of the treatment that is calculated by adding the daily
`doses reduced by the bioavailability coefficient. For example,
`the total effective dose ofCladribine corresponding to a treat(cid:173)
`ment of0.7 mg/kg Cladribine per day during 5 days wherein
`the bioavailability ofCladribine is of about 40% is 1.4 mg/kg
`35 or the total effective dose of Cladribine corresponding to a
`treatment of 0.35 mg/kg Cladribine per day during 5 days
`wherein the bioavailability of Cladribine is of about 40% is
`0.7 mg/kg.
`Typically, the bioavailability of Cladribine or of a Cladrib-
`40 ine formulation used in the context of this invention is from
`about 30% to about 90%, preferably from about 40% to about
`60%, such as about 50%.
`"A week" refers to a period of time of or about 5, about 6 or
`about 7 days.
`"A month" refers to a period of time of or about 28, about
`29, about 30 or about 31 days.
`"Treatment" comprises the sequential succession of an
`"induction treatment" and at least a "maintenance treatment".
`Typically, a treatment according to the invention comprises
`50 an "induction treatment" and about one or about two or about
`three maintenance treatments.
`Typically, a treatment according to the invention is of about
`2 years (about 24 months) or about 3 years (about 36 months)
`or about 4 years (about 48 months).
`An "Induction Treatment" consists in the sequential suc-
`cession of (i) an induction period wherein the Cladribine or
`the Cladribine pharmaceutical preparation of the invention is
`orally administered and (ii) a Cladribine-free period. An
`induction period lasts up to about 4 months or up to about 3
`60 month or up to about 2 months. For example, an induction
`period lasts for about 2 to about 4 months. An induction
`period consists in the oral administration of Cladribine or a
`pharmaceutical preparation thereof during about 1 to about 7
`days each month.
`A "Cladribine-free period" is a period wherein no Cladrib(cid:173)
`ine is administered to the patient. During a Cladribine-free
`period, the patient can be free of any administration or be
`
`4
`
`

`

`US 8,377,903 B2
`
`5
`6
`dosed with a placebo-pill or another drug except. A Cladrib(cid:173)
`T 1 enhancedhypointense lesion volume (thought to represent
`ine-free period lasts up to about 10 months or up to 9 months
`primarily demyelination and axon loss), time-to-progression
`or up to about 8 months. For example, a Cladribine-free
`of MS, frequency and severity of exacerbations and time-to(cid:173)
`period lasts from about 8 to about 10 months, typically at least
`exacerbation, Expanded Disability Status Scale score and
`Scripps Neurologic Rating Scale (SNRS) score (Sipe et al.,
`of about 8 months.
`A "Maintenance Treatment" consists in the sequential suc(cid:173)
`1984,Neurology, 34, 1368-1372). Methods of early and accu(cid:173)
`rate diagnosis of multiple sclerosis and of following the dis(cid:173)
`cession of (i) a maintenance period wherein the Cladribine or
`the Cladribine pharmaceutical preparation of the invention is
`ease progression are described in Mattson, 2002, Expert Rev.
`orally administered at a lower dose than the Cladribine dose
`Neurotherapeutics, 319-328.
`orally administered during the induction treatment and (ii) a 10
`Degree of disability of MS patients can be for example
`Cladribine-free period. A maintenance period lasts for up to
`measured by Kurtzke Expanded Disability Status Scale
`about 4 months, or up to about 3 months, or up to about 2
`(EDSS) score (Kurtzke, 1983, Neurology, 33, 1444-1452).
`months, preferably up to about 2 months. For example, a
`Typically a decrease in EDSS score corresponds to an
`maintenance period lasts for about 2 to about 4 months,
`improvement in the disease and conversely, an increase in
`preferably for about 2 months. A maintenance period consists 15 EDSS score corresponds to a worsening of the disease.
`in the oral administration ofCladribine orofa pharmaceutical
`Cladribine (2-CdA)
`2-CdA and its pharmacologically acceptable salts may be
`preparation thereof during about 1 to about 7 days each
`used in the practice of this invention.
`month.
`Cladribine can be formulated in any pharmaceutical prepa-
`Within the context of this invention, the beneficial effect,
`20 ration suitable for oral administration. Representative oral
`including but not limited to an attenuation, reduction,
`formulations of 2-CdA are described in (WO 96/19230; WO
`decrease or diminishing of the pathological development
`after onset of the disease, may be seen after one or more a
`96/19229; U.S. Pat. No. 6,194,395; U.S. Pat. No. 5,506,214;
`"treatments", after an "induction treatment", after a "mainte(cid:173)
`WO 2004/087100; WO 2004/087101), the contents of which
`nance treatment" or during a Cladribine-free period.
`are incorporated herein by reference. Examples of ingredi-
`"Daily dose" refers to the total dose of Cladribine orally
`25 ents for oral formulations are given below.
`Processes for preparing 2-CdA are well known in the art.
`administered to the patient each day of administration. The
`For example, the preparation of 2-CdA is described in (EP
`daily dose can be reached through a single or several admin(cid:173)
`istrations per day, such as for example once a day, twice a day
`173,059; WO 04/028462; WO 04/028462; U.S. Pat. No.
`or three times a day.
`5,208,327; WO 00/64918) and Robins et al., J. Am. Chem.
`30 Soc., 1984, 106: 6379. Alternatively, pharmaceutical prepa(cid:173)
`The dosage administered, as single or multiple doses, to an
`individual will vary depending upon a variety of factors,
`rations of 2-CdA may be purchased from Bedford Laborato(cid:173)
`including pharmacokinetic properties, patient conditions and
`ries, Bedford, Ohio.
`characteristics (sex, age, body weight, health, size), extent of
`Oral administration of Cladribine may be in capsule, tablet,
`symptoms, concurrent treatments, frequency of treatment and
`oral suspension, or syrup form. The tablet or capsules may
`the effect desired.
`35 contain from about 3 to 500 mg ofCladribine. Preferably they
`Patients suffering from MS can be defined for example as
`may contain about 3 to about 10 mg of Cladribine, more
`having clinically definite or laboratory-definite MS according
`preferably about 3, about 5 or about 10 mg ofCladribine. The
`to Schumacher or Poser criteria (Schumacher et al., 1965,
`capsules may be gelatin capsules and may contain, in addition
`Ann. NY Acad. Sci. 1965; 122:552-568; Poser et al., 1983,
`to Cladribine in the quantity indicated above, a small quantity,
`Ann. Neural. 13(3): 227-31).
`40 for example less than 5% by weight, magnesium stearate or
`"Relapses" involve neurologic problems that occur over a
`other excipient. Tablets may contain the foregoing amount of
`the compound and a binder, which may be a gelatin solution,
`short period, typically days but sometimes as short as hours or
`even minutes. These attacks most often involve motor, sen(cid:173)
`a starch paste in water, polyvinyl alcohol in water, etc. with a
`sory, visual or coordination problems early in the disease.
`typical sugar coating.
`Later, bladder, bowel, sexual and cognitive problems may be
`45 Compositions
`shown. Sometimes the attack onset occurs over several
`Compositions of this invention may further comprise one
`weeks. Typical MS relapse involves a period of worsening,
`or more pharmaceutically acceptable additional ingredient(s)
`with development of neurological deficits, then a plateau, in
`such as alum, stabilizers, antimicrobial agents, buffers, col(cid:173)
`oring agents, flavoring agents, adjuvants, and the like.
`which the patient is not getting any better but also not getting
`Compositions of this invention may be in the form of
`any worse followed by a recovery period. Recovery usually 50
`begins within a few weeks.
`tablets or lozenges formulated in a conventional manner. For
`"Efficacy" of a treatment according to the invention can be
`example, tablets and capsules for oral administration may
`measured based on changes in the course of disease in
`contain conventional excipients including, but not limited to,
`binding agents, fillers, lubricants, disintegrants and wetting
`response to a use according to the invention. For example,
`treatment of MS efficacy can be measured by the frequency of
`55 agents. Binding agents include, but are not limited to, syrup,
`accacia, gelatin, sorbitol, tragacanth, mucilage of starch and
`relapses in RRMS and the presence or absence of new lesions
`in the CNS as detected using methods such as MRI technique
`polyvinylpyrrolidone. Fillers include, but are not limited to,
`(Miller et al., 1996, Neurology, 47(Suppl 4): 5217; Evans et
`lactose, sugar, microcrystalline cellulose, maize starch, cal(cid:173)
`al., 1997, Ann. Neurology, 41:125-132).
`cium phosphate, and sorbitol. Lubricants include, but are not
`The observation of the reduction and/or suppression of
`60 limited to, magnesium stearate, stearic acid, talc, polyethyl(cid:173)
`ene glycol, and silica. Disintegrants include, but are not lim(cid:173)
`MRI T 1 gadolinium-enhanced lesions (thought to represent
`ited to, potato starch and sodium starch glycollate. Wetting
`areas of active inflammation) gives a primary efficacy vari(cid:173)
`agents include, but are not limited to, sodium lauryl sulfate.
`able.
`Tablets may be coated according to methods well known in
`Secondary efficacy variables include MRI T 1 enhanced
`brain lesion volume, MRI T 1 enhanced lesion number, MRI
`65 the art.
`T 2 lesion volume (thought to represent total disease burden,
`Compositions of this invention may also be liquid formu(cid:173)
`lations including, but not limited to, aqueous or oily suspen-
`i.e. demyelination, gliosis, inflanimation and axon loss), MRI
`
`5
`
`

`

`US 8,377,903 B2
`
`7
`sions, solutions, emulsions, syrups, and elixirs. The compo(cid:173)
`sitions may also be formulated as a dry product for
`constitution with water or other suitable vehicle before use.
`Such liquid preparations may contain additives including, but
`not limited to, suspending agents, emulsifying agents, non(cid:173)
`aqueous vehicles and preservatives. Suspending agent
`include, but are not limited to, sorbitol syrup, methyl cellu(cid:173)
`lose, glucose/sugar syrup, gelatin, hydroxyethylcellulose,
`carboxymethyl cellulose, aluminum stearate gel, and hydro(cid:173)
`genated edible fats. Emulsifying agents include, but are not
`limited to, lecithin, sorbitan monooleate, and acacia. Non(cid:173)
`aqueous vehicles include, but are not limited to, edible oils,
`almond oil, fractionated coconut oil, oily esters, propylene
`glycol, and ethyl alcohol. Preservatives include, but are not
`limited to, methyl or propyl p-hydroxybenzoate and sorbic 15
`acid.
`Combination
`According to the invention, Cladribine can be administered
`alone or in combination with IFN-beta, prophylactically or
`therapeutically to an individual prior to, simultaneously or
`sequentially with other therapeutic regimens or agents ( e.g.
`multiple drug regimens), in a therapeutically effective
`amount, especially therapeutic agents for the treatment of
`multiple sclerosis. Active agents that are administered simul(cid:173)
`taneously with other therapeutic agents can be administered 25
`in the same or different compositions and in the same or
`different routes of administration.
`In one embodiment, when Cladribine is administered in
`combination with IFN-beta, IFN-beta is administered during
`the Cladribine-free period.
`In another embodiment, when Cladribine is administered
`in combination with IFN-beta, IFN-beta is administered after
`the "treatment" according to the invention.
`The term "interferon-beta (IFN-~)", as used herein, is
`intended to include fibroblast interferon in particular of 35
`human origin, as obtained by isolation from biological fluids
`or as obtained by DNA recombinant techniques from
`prokaryotic or eukaryotic host cells, as well as its salts, func(cid:173)
`tional derivatives, variants, analogs and active fragments.
`IFN-~ suitable in accordance with the present invention is 40
`commercially available e.g. as Rebif® (Serano), Avonex®
`(Biogen) or Betaferon® (Schering). The use of interferons of
`human origin is also preferred in accordance with the present
`invention. The term interferon, as used herein, is intended to
`encompass salts, functional derivatives, variants, analogs and 45
`active fragments thereof.
`Rebif® (recombinant human interferon-~) is the latest
`development in interferon therapy for multiple sclerosis (MS)
`and represents a significant advance in treatment. Rebif® is
`interferon (IFN)-beta la, produced from manmialian cell 50
`lines. It was established that interferon beta-la given subcu(cid:173)
`taneously three times per week is efficacious in the treatment
`of Relapsing-Remitting Multiple Sclerosis (RRMS). Inter(cid:173)
`feron beta-la can have a positive effect on the long-term
`course of MS by reducing number and severity of relapses 55
`and reducing the burden of the disease and disease activity as
`measured by MRI.
`The dosing ofIFN-~ in the treatment ofrelapsing-remit(cid:173)
`ting MS according to the invention depends on the type of
`IFN-~ used.
`In accordance with the present invention, where IFN is
`recombinant IFN-~lb produced in E. Coli, commercially
`available under the trademark Betaseron®, it may preferably
`be administered sub-cutaneously every second day at a dos(cid:173)
`age of about of 250 to 300 µgor8 MIU to 9.6 MIU per person. 65
`In accordance with the present invention, where IFN is
`recombinant IFN-~la, produced in Chinese Hamster Ovary
`
`8
`cells (CHO cells), commercially available under the trade(cid:173)
`markAvonex®, it may preferably be administered intra-mus(cid:173)
`cularly once a week at a dosage of about of30 µg to 33 µg or
`6 MIU to 6.6 MIU per person.
`In accordance with the present invention, when IFN is
`recombinant IFN-~la, produced in Chinese Hamster Ovary
`cells (CHO cells), commercially available under the trade(cid:173)
`mark Rebif®, it may preferably be administered sub-cutane(cid:173)
`ously three times a week (TIW) at a dosage of 22 to 44 µg or
`10 6 MIU to 12 MIU per person.
`Patients
`Patients according to the invention are patients suffering
`from multiple sclerosis, preferably RRMS or early SPMS.
`In an embodiment of the invention, patients are selected
`from human males or