USOO7713947B2
`
`(12) United States Patent
`De Luca et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,713,947 B2
`May 11, 2010
`
`(54) CLADRIBINE REGIMEN FORTREATING
`MULTIPLE SCLEROSIS
`
`1/2010 Brentzel et al. ............ 424,856
`2010, 0021429 A1
`FOREIGN PATENT DOCUMENTS
`
`(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 S.A., Coinsins, Vaud
`(CH)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 300 days.
`11/722,018
`
`(21) Appl. No.:
`
`(*) Notice:
`
`(22) PCT Filed:
`(86). PCT No.:
`
`Dec. 20, 2005
`PCT/EP2005/056954
`
`S371 (c)(1),
`Jun. 18, 2007
`(2), (4) Date:
`(87) PCT Pub. No.: WO2006/067141
`PCT Pub. Date: Jun. 29, 2006
`
`(65)
`
`Prior Publication Data
`US 2009/0081163 A1
`Mar. 26, 2009
`
`Related U.S. Application Data
`(60) Provisional application No. 60/638,669, filed on Dec.
`22, 2004.
`Foreign Application Priority Data
`(30)
`Dec. 22, 2004 (EP) .................................. O4106909
`(51) Int. Cl.
`(2006.01)
`A6 IK3I/52
`(2006.01)
`A 6LX 3L/7076
`(2006.01)
`A6 IK 38/2
`(2006.01)
`A61 K9/00
`(52) U.S. Cl. ........................................ 514/46; 424/85.6
`(58) Field of Classification Search ....................... None
`See application file for complete search history.
`References Cited
`
`(56)
`
`U.S. PATENT DOCUMENTS
`
`4,964,848 A * 10, 1990 Bloom ...................... 604f6.03
`5,506,214. A
`4, 1996 Beutler ........................ 514.46
`
`4/2000
`O 626 853 B1
`EP
`WO WO 2004/087101 A2 10, 2004
`
`OTHER PUBLICATIONS
`Beutler, E. etal. “Marrow Suppression Produced by Repeated Doses
`of Cladribine”. Acta Haematol, 1994, pp. 10-15, vol. 91.
`Beutler, E. etal. “Treatment of Multiple Sclerosis and Other Autoim
`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. etal. “Oral Cladribine for Multiple Sclerosis'. Neurology,
`Mar. 1997, P03,070, pp. A 174-A175, vol. 48, No. 3, XPO08047069.
`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.
`Kazimierczuk, Z. et al. “Synthesis of 2'-Deoxytubercidin,
`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
`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.
`
`(Continued)
`Primary Examiner Elizabeth C. Kemmerer
`Assistant Examiner Kimberly A. Ballard
`(74) Attorney, Agent, or Firm Saliwanchik, Lloyd &
`Saliwanchik
`
`(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 orally administered and
`wherein re-treatments are possible.
`
`48 Claims, No Drawings
`
`Petitioner TWi Pharms., Inc.
`EX1001, Page 1 of 13
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`

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`US 7,713,947 B2
`Page 2
`
`OTHER PUBLICATIONS
`Mattson, D. "Update on the diagnosis of multiple sclerosis'. Expert
`Review of Neurotherapeutics, May 2002, pp. 319-327, vol. 2, No. 3.
`McDonald, W. etal. “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. etal. “Therapeutic advances in ALS'. 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 of Cladribine in Relapsing-Remitting Multiple Sclerosis'. Pro
`ceedings of the Association of American Physicians, Jan./Feb. 1999,
`pp. 35-44, vol. 111, No. 1.
`Schumacher, G. etal. “Problems of Experimental Trials of Therapy in
`Multiple Sclerosis: Report by the Panel on the Evaluation of Experi
`mental Trials of Therapy in Multiple Sclerosis'. Annals New York
`Academy of Sciences, Mar. 31, 1965, pp. 552-568, vol. 122.
`Selby, R. et al. “Safety and Tolerability of Subcutaneous Cladribine
`Therapy in Progressive Multiple Sclerosis', Can. J. Neurol. 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
`of cladribine
`(2-chlorodeoxyadenosine) in remitting-relapsing multiple Sclero
`sis'. Med. Sci Monit., 1998, pp. 4-8, vol. 4. No. 1.
`* cited by examiner
`
`Petitioner TWi Pharms., Inc.
`EX1001, Page 2 of 13
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`

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`US 7,713,947 B2
`
`1.
`CLADRBINE REGIMIEN FOR TREATING
`MULTIPLE SCLEROSIS
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application is the U.S. national stage application of
`International Patent Application No. PCT/EP2005/056954,
`filed Dec. 20, 2005, which claims the benefit of U.S. Provi
`sional 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
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`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
`gressive multiple Sclerosis.
`
`BACKGROUND OF THE INVENTION
`
`2
`cations for disease classification (Lassmann et al., 2001,
`Trends Mol. Med., 7, 115-121; Lucchinetti et al., Curr. Opin.
`Neurol., 2001, 14, 259-269).
`MS onset is defined by the occurrence of the first neuro
`logical symptoms of CNS dysfunction. Advances in cere
`broSpinal fluid (CSF) analysis and magnetic resonance imag
`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
`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. Neurol., 50:121-127).
`Current medications for MS which are disease modifying
`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(R), Berlex: Avonex R, Biogen; RebifR), Serono)
`and Glatimarer Acetate (Copaxone R, Amgen). There is also
`one FDA approved immunosuppressing drug for worsening
`MS, Mitoxantrone (Novantrone(R), Amgen). Several other
`immunosuppressive agents are used, although not FDA
`approved.
`Among them, Cladribine, a chlorinated purine analogue
`2-chloro-2'deoxyadenosine analogue (2-CdA), has been Sug
`gested to be useful in the treatment of MS (EP626853B1 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.
`Cladribine in MS.
`Two double-blind, placebo controlled Phase II studies
`were conducted respectively in the treatment of Chronic Pro
`gressive MS (Selby et al., 1998, Can. J. Neurol. Sci., 25:295
`299) and Relapsing-Remitting MS respectively (Romine et
`al., 1999, Proceedings of the Association of American Physi
`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
`ducted in patients with primary progressive (PP) or secondary
`progressive (SP) multiple sclerosis (Rice at al., 2000, Neurol
`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
`nance Imaging (MRI) findings (Beutler et al., 1996, Proc.
`Nat. Acad. Sci. USA, 93, 1716-1720; Romine et al., 1999
`above). Phase II study results, were positive on the significant
`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 eitheri.V. or s.c. administration. As a result,
`Beutler et al. (Beutler et al., 1996, Seminars in Hematology,
`
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`Multiple sclerosis (MS) is the most known chronic inflam
`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 is disability in MS is pre
`sumed to be a result of repeated inflammatory injury with
`Subsequent loss of myelin and axons, leading to tissue atro
`phy.
`MS is manifested in physical symptoms (relapses and dis
`ability progression), Central Nervous System (CNS) inflam
`mation, brain atrophy and cognitive impairment. Presenting
`symptoms include focal sensory deficits, focal weakness,
`visual problems, imbalance and fatigue. Sexual impairment
`and sphincter dysfunction may occur. Approximately half of
`40
`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
`exacerbations. Remissions vary in length and may last several
`years but are infrequently permanent.
`Four courses of the disease are individualized: relapsing
`remitting (RR), secondary progressive (SP), primary progres
`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
`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
`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
`ous progression between exacerbations (Lublin and Reingold
`above). 10% of MS patients have PPMS which is character
`ized by insidious progression of the symptoms from the dis
`ease onset. Less than 5% of patients have PRMS and are often
`considered to have the same prognosis as PPMS. It is sug
`gested that distinct pathogenic mechanisms may be involved
`in different patient Sub-groups and have wide-ranging impli
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`EX1001, Page 3 of 13
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`US 7,713,947 B2
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`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.
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`DETAILED DESCRIPTION OF THE INVENTION
`
`3
`33, 1(S1), 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
`ting-relapsing multiple sclerosis (Grieb et al., 1995, Archi
`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
`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
`cumulative dose of 0.4–0.66 mg/kg after a cladribine free
`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
`gressive multiple sclerosis treated by i.v. infusion of Cladrib
`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
`tified (Stelmasiak et al., 1998, Laboratory Investigations,
`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
`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 of Cladribinetreatment between the treat
`ment periods is also desirable.
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`SUMMARY OF THE INVENTION
`
`The present invention is directed towards a use of Cladrib
`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
`of Cladribine for the preparation of a pharmaceutical formu
`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
`tion wherein the formulation is to be orally administered
`following the sequential steps below:
`(i) An induction period wherein the Cladribine pharmaceu
`tical formulation is administered and 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 period wherein Cladribine pharmaceu
`tical formulation is administered and 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.
`In another embodiment, the invention provides a method
`for the treatment of multiple Sclerosis, comprising the oral
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`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
`ine 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.
`“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
`end of the treatment that is calculated by adding the daily
`doses reduced by the bioavailability coefficient. For example,
`the total effective dose of Cladribine corresponding to a treat
`ment of 0.7 mg/kg. Cladribine per day during 5 days wherein
`the bioavailability of Cladribine is of 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
`wherein the bioavailability of Cladribine is of about 40% is
`0.7 mg/kg.
`Typically, the bioavailability of Cladribine or of a Cladrib
`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
`an “induction treatment” and about one or about two or about
`three maintenance treatments. Typically, a treatment accord
`ing 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
`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
`ine is administered to the patient. During a Cladribine-free
`period, the patient can be free of any administration or be
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`Petitioner TWi Pharms., Inc.
`EX1001, Page 4 of 13
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`5
`dosed with a placebo-pill or another drug except. A Cladrib
`ine-free period lasts up to about 10 months or up to 9 months
`or up to about 8 months. For example, a Cladribine-free
`period lasts from about 8 to about 10 months, typically at least
`of about 8 months.
`A“Maintenance Treatment consists in the sequential Suc
`cession of (i) a maintenance period wherein the Cladribine or
`the Cladribine pharmaceutical preparation of the invention is
`orally administered at a lower dose than the Cladribine dose
`orally administered during the induction treatment and (ii) a
`Cladribine-free period. A maintenance period lasts for 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, a
`maintenance period lasts for about 2 to about 4 months,
`preferably for about 2 months. A maintenance period consists
`in the oral administration of Cladribine or of a pharmaceutical
`preparation thereof during about 1 to about 7 days each
`month.
`Within the context of this invention, the beneficial effect,
`including but not limited to an attenuation, reduction,
`decrease or diminishing of the pathological development
`after onset of the disease, may be seen after one or more a
`“treatments', after an “induction treatment, after a “mainte
`nance treatment” or during a Cladribine-free period.
`“Daily dose' refers to the total dose of Cladribine orally
`administered to the patient each day of administration. The
`daily dose can be reached through a single or several admin
`istrations per day, Such as for example once a day, twice a day
`or three times a day.
`The dosage administered, as single or multiple doses, to an
`individual will vary depending upon a variety of factors,
`including pharmacokinetic properties, patient conditions and
`characteristics (sex, age, body weight, health, size), extent of
`symptoms, concurrent treatments, frequency of treatment and
`the effect desired.
`Patients suffering from MS can be defined for example as
`having clinically definite or laboratory-definite MS according
`to 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).
`“Relapses' involve neurologic problems that occur over a
`short period, typically days but sometimes as short as hours or
`even minutes. These attacks most often involve motor, sen
`sory, visual or coordination problems early in the disease.
`Later, bladder, bowel, sexual and cognitive problems may be
`shown. Sometimes the attack onset occurs over several
`weeks. Typical MS relapse involves a period of worsening,
`with development of neurological deficits, then a plateau, in
`which the patient is not getting any better but also not getting
`any worse followed by a recovery period. Recovery usually
`begins within a few weeks.
`“Efficacy' of a treatment according to the invention can be
`measured based on changes in the course of disease in
`response to a use according to the invention. For example,
`treatment of MS efficacy can be measured by the frequency of
`relapses in RRMS and the presence or absence of new lesions
`in the CNS as detected using methods such as MRI technique
`(Miller et al., 1996, Neurology, 47(Suppl 4): S217: Evans et
`al., 1997, Ann. Neurology, 41:125-132).
`The observation of the reduction and/or suppression of
`MRIT gadolinium-enhanced lesions (thought to represent
`areas of active inflammation) gives a primary efficacy vari
`able.
`Secondary efficacy variables include MRI T enhanced
`brain lesion volume, MRIT enhanced lesion number, MRI
`T. lesion Volume (thought to represent total disease burden,
`i.e. demyelination, gliosis, inflammation and axon loss), MRI
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`US 7,713,947 B2
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`T enhanced hypointense lesion Volume (thought to represent
`primarily demyelination and axon loss), time-to-progression
`of MS, frequency and severity of exacerbations and time-to
`exacerbation, Expanded Disability Status Scale score and
`Scripps Neurologic Rating Scale (SNRS) score (Sipe et al.,
`1984, Neurology, 34, 1368-1372). Methods of early and accu
`rate diagnosis of multiple Sclerosis and of following the dis
`ease progression are described in Mattson, 2002, Expert Rev.
`Neurotherapeutics, 319-328.
`Degree of disability of MS patients can be for example
`measured by Kurtzke Expanded Disability Status Scale
`(EDSS) score (Kurtzke, 1983, Neurology, 33, 1444-1452).
`Typically a decrease in EDSS score corresponds to an
`improvement in the disease and conversely, an increase in
`EDSS score corresponds to a worsening of the disease.
`Cladribine (2-CdA)
`2-CdA and its pharmacologically acceptable salts may be
`used in the practice of this invention.
`Cladribine can beformulated in any pharmaceutical prepa
`ration suitable for oral administration. Representative oral
`formulations of 2-CdA are described in (WO 96/19230; WO
`96/19229; U.S. Pat. Nos. 6,194,395; 5,506,214; WO 2004/
`087100; WO 2004/087101), the contents of which are incor
`porated herein by reference. Examples of ingredients for oral
`formulations are given below.
`Processes 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; U.S. Pat. No.
`5,208,327; WO 00/64918) and Robins et al., J. Am. Chem.
`Soc., 1984, 106: 6379. Alternatively, pharmaceutical prepa
`rations of 2-CdA may be purchased from Bedford Laborato
`ries, Bedford, Ohio.
`Oral administration of Cladribine may be incapsule, tablet,
`oral Suspension, or syrup form. The tablet or capsules may
`contain from 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
`capsules may be gelatin capsules and may contain, in addition
`to Cladribine in the quantity indicated above, a small quantity,
`for example less than 5% by weight, magnesium Stearate or
`other excipient. Tablets may contain the foregoing amount of
`the compound and a binder, which may be a gelatin solution,
`a starch paste in water, polyvinyl alcohol in water, etc. with a
`typical Sugar coating.
`Compositions
`Compositions of this invention may further comprise one
`or more pharmaceutically acceptable additional ingredient(s)
`Such as alum, stabilizers, antimicrobial agents, buffers, col
`oring agents, flavoring agents, adjuvants, and the like.
`Compositions of this invention may be in the form of
`tablets or lozenges formulated in a conventional manner. For
`example, tablets and capsules for oral administration may
`contain conventional excipients including, but not limited to,
`binding agents, fillers, lubricants, disintegrants and wetting
`agents. Binding agents include, but are not limited to, syrup,
`accacia, gelatin, Sorbitol, tragacanth, mucilage of starch and
`polyvinylpyrrolidone. Fillers include, but are not limited to,
`lactose, Sugar, microcrystalline cellulose, maizestarch, cal
`cium phosphate, and Sorbitol. Lubricants include, but are not
`limited to, magnesium Stearate, Stearic acid, talc, polyethyl
`ene glycol, and silica. Disintegrants include, but are not lim
`ited to, potato starch and sodium starch glycollate. Wetting
`agents include, but are not limited to, Sodium lauryl Sulfate).
`Tablets may be coated according to methods well known in
`the art.
`
`Petitioner TWi Pharms., Inc.
`EX1001, Page 5 of 13
`
`

`

`US 7,713,947 B2
`
`7
`Compositions of this invention may also be liquid formu
`lations including, but not limited to, aqueous or oily Suspen
`sions, solutions, emulsions, syrups, and elixirs. The compo
`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
`aqueous vehicles and preservatives. Suspending agent
`include, but are not limited to, sorbitol syrup, methyl cellu
`lose, glucose/Sugar syrup, gelatin, hydroxyethylcellulose,
`carboxymethyl cellulose, aluminum Stearate gel, and hydro
`genated edible fats. Emulsifying agents include, but are not
`limited to, lecithin, Sorbitan monooleate, and acacia. Non
`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
`acid.
`
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`8
`be administered sub-cutaneously every second day at a dos
`age of about of 250 to 300 ug or 8MIU to 9.6MIU perperson.
`In accordance with the present invention, where IFN is
`recombinant IFN-?31a, produced in Chinese Hamster Ovary
`cells (CHO cells), commercially available under the trade
`mark Avonex R, it may preferably be administered intramus
`cularly once a week at a dosage of about of 30 ug to 33 ug or
`6 MIU to 6.6 MIU per person.
`In accordance with the present invention, when IFN is
`recombinant IFN-?31a, produced in Chinese Hamster Ovary
`cells (CHO cells), commercially available under the trade
`mark RebifR), it may preferably be administered sub-cutane
`ously three times a week (TIW) at a dosage of 22 to 44 ug or
`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 females between 18 and 55 years age.
`In another embodiment of the invention, patients had at
`least one relapse within the prior 12 months of the treatment.
`Use According to the Invention
`In one embodiment, the invention provides a use of
`Cladribine for the preparation of a pharmaceutical formula
`tion for the treatment of multiple sclerosis wherein the for
`mulation is to be orally administered following the sequential
`steps below:
`(i) An induction period wherein Cladribine pharmaceutical
`formulation is administered and 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 period wherein Cladribine pharmaceu
`tical formulation is administered and 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.
`In a further embodiment, the invention provides a 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.
`In a further embodiment, the invention provides a use
`according to the invention wherein the induction period lasts
`up to about 2 months.
`In a further embodiment, the invention provides a use
`according to the invention wherein the induction period lasts
`up to about 4 months.
`In a further embodiment, the invention provides a use
`according to the invention wherein the total dose of Cladrib
`ine reached at the end of the induction period is about 1.7
`mg/kg.
`In a further embodiment, the invention provides a use
`according to the invention wherein the total dose of Cladrib
`ine reached at the end of the induction period is about 3.5
`mg/kg.
`In another further embodiment, the invention provides a
`use according to the invention wherein the Cladribine-free
`period lasts up to about 10 months, or up to about 9 months or
`up to about 8 months.
`In another further embodiment, the invention provides a
`use according to the invention wherein the Cladribine-free (ii)
`period lasts up to about 8 months.
`
`25
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`30
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`35
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`40
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`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
`taneously with other therapeutic agents can be administered
`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 WFN-beta, WFN-beta is administered dur
`ing the Cladribine-f