(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`19 July 2007 (19.07.2007)
`
`(51) International Patent Classification:
`A61K 38116 (2006.01)
`
`PCT
`
`(10) International Publication Number
`WO 2007/081975 A2
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS,
`JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
`LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY,
`MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS,
`RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`(21) International Application Number:
`PCT/US2007 /000575
`
`(22) International Filing Date: 9 January 2007 (09.01.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`601758,580
`
`11 January 2006 (11.01.2006) US
`
`(71) Applicant (for all designated States except BB, US):
`TEVA PHARMACEUTICAL INDUSTRIES, LTD.
`[IL/IL]; 5 Basel Street, P.O. Box 3190, 49131 Petach-Tikva
`(IL).
`
`(71) Applicant (for BB only): TEVA PHARMACEUTICALS
`USA, INC. [US/US]; 1090 Horsham Road, North Wales,
`Pennsylvania 19454 (US).
`
`(72) Inventor: PINCHAS!, Irit; 43 Brandeis Street, Ra'anana
`(IL).
`
`(74) Agent: WHITE, John, P.; Cooper & Dunham LLP, 1185
`Avenue of the Americas, New York, NY 10036 (US).
`
`iiiiiiii
`
`-iiiiiiii
`iiiiiiii --!!!!!!!!
`---
`
`iiiiiiii
`!!!!!!!!
`
`!!!!!!!!
`iiiiiiii
`
`iiiiiiii ----
`
`.......... ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`
`ln
`r-....
`°"
`,....i
`QO
`Q
`~ (54) Title: METHOD OF TREATING MULTIPLE SCLEROSIS
`Q
`M (57) Abstract: This invention provides a method of alleviating a symptom of a patient suffering from a relapsing form of multiple
`0 sclerosis which comprises periodically administering to the patient by subcutaneous injection a single dose of a pharmaceutical
`> composition comprising 40 mg of glatiramer acetate so as to thereby alleviate the symptom of the patient. This invention also
`
`~ provides a method of reducing Gd-enhancing lesions in the brain and a pharmaceutical composition in a unit dosage.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 1
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`

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`WO 2007/081975
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`PCT/US2007/000575
`
`METHOD OF TREATING MULTIPLE SCLEROSIS
`
`5
`
`this application various publications are
`Throughout
`referenced by their full citations.
`The disclosures of
`these publications
`in
`their entireties
`are
`hereby
`incorporated by reference into this application in order
`to more fully describe the state of the art to which this
`invention pertains.
`
`10 Backqround Of The :Invention
`
`in
`the more common chronic neurologic diseases
`One of
`human adults · is multiple sclerosis
`("MS") .
`MS
`is a
`chronic,
`inflammatory
`CNS
`disease
`characterized
`pathologically
`by
`demyelination.
`has
`also
`MS
`been
`classified as an autoimmune disease. MS disease activity
`can be monitored by magnetic resonance imaging
`(MRI) of
`the brain, accumulation of disability, as well as rate and
`severity of relapses.
`
`15
`
`20
`
`There are five main forms of multiple sclerosis:
`1) benign
`sclerosis;
`multiple
`relapsing-remitting
`multiple
`2)
`(RRMS);
`sclerosis
`secondary progressive
`multiple
`3)
`(SPMS);
`sclerosis
`primary
`progressive
`multiple
`4)
`sclerosis
`(PPMS); and 5} progressive-relapsing
`multiple
`sclerosis
`(PRMS)
`(What
`are
`the Types
`of
`Multiple
`Sclerosis?,
`<http://imaginis.com/multiple-
`2005
`sclerosis/types-of-ms.asp? mode=l>).
`Chronic progressive
`multiple sclerosis is a term used to collectively-refer to
`SPMS, PPMS, and PRMS
`(Types of Multiple Sclerosis
`(MS),
`2005 <http://www.themcfox.com/multiple-sclerosis/types-of-
`30 ms/
`types-of-multiple-sclerosis. htm>) .
`The
`relapsing
`
`25
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 2
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`

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`
`PCT/US2007/000575
`
`-2-
`
`forms of multiple sclerosis are SPMS with superimposed
`relapses, RRMS and PRMS.
`
`5
`
`retrospective diagnosis
`Benign multiple sclerosis is a
`which is characterized by 1-2 exacerbations with complete
`recovery, no lasting disability and no disease progression
`for 10-15 years after the initial onset. Benign multiple
`sclerosis may,
`however, progress
`into other
`forms of
`multiple
`sclerosis.
`Patients
`suffering
`from
`RRMS
`experience sporadic exacerbations or relapses, as well as
`periods of remission. Lesions and evidence of axonal loss
`may or may not be visible on MRI for patients with RRMS.
`SPMS may evolve from RRMS.
`Patients afflicted with SPMS
`have relapses,
`a diminishing degree of recovery during
`remissions,
`less frequent remissions and more pronounced
`neurological deficits
`than RRMS patients.
`Enlarged
`ventricles I which are markers for atrophy Of the corpus
`callosum, midline center and spinal cord, are visible on
`MRI of patients with SPMS.
`PPMS
`is characterized by a
`steady progression of
`increasing neurological deficits
`20 without distinct attacks or remissions. Cerebral lesions,
`diffuse spinal cord damage and evidence of axonal loss are
`evident on
`the MRI of patients with PPMS.
`PRMS has
`periods of acute exacerbations while proceeding along a
`course
`of
`increasing
`neurological deficits without
`· remissions.
`Lesions are evident on MRI of patients
`suffering from PRMS
`(Multiple sclerosis: its diagnosis,
`symptoms,
`types
`and
`stages,
`2003
`<http://www.albany.net/-tjc/multiple-sclerosis.html>}.
`
`10
`
`15
`
`25
`
`30
`
`(GA), a mixture of polypeptides which
`Glatirarner acetate
`do not all have the same amino acid sequence, is marketed
`under the tradenarne Copaxone®. GA comprises the acetate
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 3
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`

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`WO 2007/081975
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`PCT/US2007/000575
`
`-3-
`
`salts of polypeptides containing L-glutamic acid, L-
`average molar
`and L-lysine at
`alanine, L-tyrosine
`fractions of 0.141, 0.427, 0.095 and 0.338, respectively ..
`The average molecular weight of Copaxone® is between 5,000
`daltons.
`{"Copaxone",
`Physician's
`Desk
`9,000
`and
`Reference,
`(2005), Medical Economics Co., Inc., (Montvale,
`NJ),. 3115.) Chemically, glatiramer acetate is designated
`L-glutamic acid polymer
`with L-alanine, L-lysine,
`L-
`tyrosine, acetate (salt).
`Its structural formula is:
`
`(Glu, Ala, Lys, Tyr)x•xCH3COOH
`{C5H9N04 •C3H1N02 •C6H14N202 •CsH11N03} x • XC2H402
`GAS - 147245-92-9
`
`5
`
`IO
`
`(2000), Medical
`("Copa:x:one", Physician's Desk Reference,
`Economics Co., Inc.,
`(Montvale, NJ), 3115.) Copaxone® (20
`15 mg glatiramer acetate injection} is an approved therapy
`for patients with relapsing remitting rnul tiple sclerosis
`(RRMS).
`
`Glatiramer acetate has also been disclosed for use in the
`treatment of other
`autoinunune diseases
`(U.S. Patent
`20 Publication No.
`2002/0055466 Al
`(R. Aharoni et al.),
`diseases
`inflammatory
`non-autoimmune
`Patent
`(U.S.
`Publication No. 2005/0014694 Al
`(V. Wee Yong et al.); and
`U.S. Patent Application No. 2002/0077278 Al, published
`June 20, 2002
`(Young et al.)) and other diseases
`(U.S.
`25 Patent Publication Nos. 2003/0004099 Al and 2002/0037848
`Al (Eisenbach-Schwartz, et al.); U.S. Patent No. 6,514,938
`issued
`February
`(~ad et
`2003
`al.);
`PCT
`4,
`Bl,
`International
`Publication
`No. WO
`01/60392,
`published
`August 23,
`2001
`(Gilbert et al.); PCT
`International
`Publication No. WO
`00/27417, published May 19,
`2000
`
`30
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 4
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`

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`WO 2007/081975
`
`PCT/US2007/000575
`
`-4-
`
`(Aharoni et al.); and PCT International Publication No. WO
`01/97846, published December 27, 2001 {Moses et al.)).
`
`s
`
`10
`
`The 20mg/day subcutaneous dose has been shown to reduce
`the total number of enhancing lesions in MS patients as
`measured by MRI
`(G. Comi et al., European/Canadian
`Multicenter, Double-Blind, Randomized, Placebo-Controlled
`Study of the Effects of Glatiramer Acetere on Magnetic
`Resonance Imaging-Measured Disease Activity and Burden in
`Patients with Relapsing Multiple Sclerosis, Ann. Neurol.
`49:290-297
`(2001)). However, disclosed herein
`is
`the
`finding that administration of glatiramer acetate at a dose
`of 40 mg/day significantly improves efficacy but does not
`in'
`corresponding
`have
`increase
`adverse
`reactions
`a
`experienced by the patient.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 5
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`

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`WO 2007/081975
`
`PCT/US2007/000575
`
`-5-
`
`Summary of the Invention
`
`5
`
`This invention provides a method of alleviating a symptom
`of a patient suffering from a relapsing form of multiple
`sclerosis which comprises periodically administering
`to
`the patient by subcutaneous injection a single dose of a
`pharmaceutical composition comprising 40 mg of glatiramer
`acetate so as
`to thereby alleviate the symptom of the
`patient.
`
`invention· also ·provides a method of reducing MRI-
`This
`10 monitored disease activity and burden of~ a patient
`suffering
`comprises
`from multiple
`sclerosis which
`periodically administering to the patient by subcutaneous
`injection a single dose of a pharmaceutical composition
`comprising 40 mg of glatiramer acetate.
`
`15
`
`20
`
`I
`
`provides
`further
`invention
`This
`pharmaceutical
`a
`composition in a unit dosage injectable form comprising 40
`mg of glatiramer acetate and a pharmaceutically acceptable
`carrier.
`
`This invention also provides a use of glatiramer acetate
`the manufacture of
`in
`pharmaceutical
`composition
`a
`comprising a 40 mg glatiramer acetate for subcutaneous
`administration to alleviate a symptom of a relapsing form
`of multiple sclerosis in a human patient.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 6
`
`

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`WO 2007/081975
`
`PCT/US2007/000575
`
`-6-
`
`Brief Description of the Figures
`
`Figure 1. Mean ± SE Of Tl Gd-Enhancing Lesions by Month -
`Mean ± SE of Tl Gd-enhancing lesions by month comparing 20
`mg and 40 mg per day GA dosages.
`
`(N=81) Cumulative
`ITT Cohort
`5 Figure 2. Primary Analysis:
`Number of Tl-Enhancing Lesions at Months 7, 8 and 9
`primary analysis of the cumulative number of Tl Gd-enhanced
`lesions at months 7, 8, and 9 comparing 20 mg and 40 mg per
`day GA dosages ·for· the ITT cohort (n=81).
`
`10 Figure 3. Post Hoc Analysis:
`(N=84) Cumulative Number
`ITT
`of Tl GD-Enhancing Lesions at Month 3
`- Post-hoc analysis
`of the cumulative number of Tl-enhanceing lesions at month
`3 for
`ITT
`(n=84) comparing 20 mg and 40 mg per day GA
`dosages.
`
`15 Figure 4. Number ·of Confirmed Relapses on Trial - Graphic
`comparison of the number of confirmed relapse in the trial
`between the 20 mg GA per day and 40 mg GA per day dosage
`groups.
`
`20
`
`Figure 5. Time
`to First Confirmed Relapse
`Graphic
`comparison of the time to first confirmed relapse between
`the 20 GA mg per day and 40 mg GA per day dosage groups.
`
`Figure 6. Mean ± SE of New T2 Lesions by Month - A graphic
`comparison of the mean ± SE new lesions by month between
`the 20 mg GA per day and the 40 mg GA per day dosage
`groups.
`
`25
`
`Figure 7. Cumulative Number of New T2 Gd-Enhancing Lesions
`at Months 8 and 9
`(N=81)
`-
`a graphic comparison of the
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 7
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`

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`WO 2007/081975
`
`PCT/US2007/000575
`
`-7-
`
`the cumulative number of new T2 Gd(cid:173)
`adjusted means of
`enhancing lesions at months 8 and 9 between the 20 mg GA
`per day and 40 mg GA per day dosage groups.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 8
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`

`
`WO 2007/081975
`
`PCT/US2007/000575
`
`-8-
`
`Detai1ed Description of the rnvention
`
`This invention provides a method of alleviating a symptom
`
`5
`
`of a patient suffering from a relapsing form of multiple
`sclerosis which comprises periodically administering
`to
`the patient by subcutaneous injection a single dose of a
`pharmaceutical compositi9n comprising 40 mg of glatiramer
`acetate so as
`to thereby alleviate the symptom of the
`
`patient.
`
`In an embodiment, the periodic administration is daily.·
`
`10
`
`In another embodiment,
`every other day.
`
`the periodic administration
`
`is
`
`In yet another embodiment, the relapsing form o:E multiple
`sclerosis is relapsing-remitting multiple sclerosis.
`
`In a further embodiment,
`relapses.
`
`15
`
`the symptom is the frequency of
`
`In an embodiment, the pharmaceutical composition is in the
`form of a sterile solution.
`
`the pharmaceutical composition
`In· another embodiment,
`further comprises mannitol.
`
`20
`
`the pharmaceutical composition
`In yet another embodiment,
`has a pH in the range of 5.5 to 8.5. In an embodiment, the
`
`pharmaceutical compo~ition has a pH in the range of 5.5 to
`7.0.
`
`25
`
`In a further embodiment, the pharmaceutical composition is
`in a prefilled syringe and is self-administered by the
`patient.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 9
`
`

`
`WO 2007/081975
`
`PCT/US2007/000575
`
`-9-
`
`5
`
`IO
`
`15
`
`20
`
`25
`
`invention also provides a method of reducing MRI(cid:173)
`This
`monitored disease activity and burden of
`a patient
`comprises
`suffering
`sclerosis which
`from multiple
`periodically administering to the patient by subcutaneous
`injection a single dose of a pharmaceutical composition
`comprising 40 mg of glatiramer acetate.
`
`In an embodiment, reducing MRI-monitored disease activity
`and burden is reducing the n1ean cumulative number of Gd(cid:173)
`enhancing lesions in the brain of the patient.
`
`reducing MRI-monitored disease
`In another embodiment,
`activity and burden is reducing the mean number of new T2
`lesions in the brain of the patient.
`
`the
`the method,
`the above embodiments of
`In any of
`periodic administration to the patient of the single dose
`a
`.pharmaceutical composition comprising 40 mg of
`of
`glatiramer acetate further reduces a symptom of MS.
`In an
`embodiment, the symptom may be the frequency of relapses.
`
`In any embodiment of a method of reducing MRI-monitored
`disease activity and burden,
`the periodic administration
`is daily. The periodic-administration may alternatively be
`every other day.
`
`the patient is
`the method,
`In further embodiments of
`s~ffering from a relapsing form of multiple sclerosis.
`In
`an embodiment, the relapsing form of multiple sclerosis is
`relapsing-remitting multiple sclerosis.
`
`the pharmaceutical
`In further embodiments of the method,
`composition is in the form of a sterile solution.
`
`In
`
`yet
`
`further
`
`embodiments
`
`of
`
`the method,
`
`the
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 10
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`

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`WO 2007/081975
`
`PCT/US2007/000575
`
`·'
`pharmaceutical composition further comprises mannitol.
`
`-10-
`
`S
`
`10
`
`the pharmaceutical
`In further embodiments of t.he method,
`cornposi tion has a pH
`in the range of 5. 5 to 8. 5. In an
`embodiment,
`the pharmaceutical composition may have a pH
`in the range of 5.5 to 7.0.
`
`In a further embodiment of the method, the pharmaceutical
`is self(cid:173)
`composition
`is
`in
`a prefilled syringe and
`administered by the patient.
`
`This
`provides
`pharmaceutical
`further
`invention
`a
`composition in a unit dosage injectable form comprising 40
`mg of glatiramer acetate and a pharmaceutically acceptable
`carrier.
`
`In an embodiment, the pharmaceutical composition·is in the
`form of a sterile solution.
`
`15
`
`In another embodiment,
`carrier is mannitol.
`
`the pharmaceutically acceptable
`
`the pharmaceutical composition
`In yet another embodiment,
`has a pH in the range of 5.5 to 8.5.
`In an embodiment,
`the pharmaceutical composition may have a pH in the range
`0 f 5 • 5 t 0 7 • 0 •
`
`In a further embodiment,
`is in a prefilled syringe.
`
`the pharmaceutical compositions
`
`This invention also provides a use of glatiramer acetate
`in
`the manufacture of
`pharmaceutical
`composition
`a
`comprising a
`40 mg glatiramer acetate for subcutaneous
`administration to alleviate a symptom of a relapsing form
`of multiple sclerosis in a human patient.
`
`20
`
`25
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 11
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`

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`
`-11-
`
`In an embodiment of
`sclerosis
`multiple
`sclerosis.
`
`form of
`relapsing
`the
`the use,
`relapsing-remitting multiple
`is
`
`In another embodiment of
`frequency of relapses.
`
`5
`
`the use,
`
`the symptom is
`
`the
`
`the pharmaceutical
`In a further embodiment of the use,
`composition is in the form of a sterile solution for once
`daily administration.
`
`the
`·of
`embodiment
`the
`use,
`an
`In
`composition further comprises mannitol.
`
`10
`
`pharmaceutical · -~
`
`the pharmaceutical
`the use,
`In another embodiment of
`composition is in the form of a sterile solution having a
`pH
`the
`range 5.5
`to 8.5.
`In an embodiment,
`the
`in
`pharmaceutical composition is the in the form of a sterile
`solution having a pH in the range 5.5 to 7.0.
`
`In yet another embodiment of the use, the pharmaceutical
`composition is in a prefilled syringe.
`
`Definitions
`
`irmnediate post injection reaction
`As used herein,
`(IRPR)
`refers to a
`reaction such as, palpitations, feeling hot,
`flushing,
`hot
`flushes,
`tachycardia,
`dyspnoea,
`chest
`discomfort, chest pain, and non-cardiac chest pain that
`occurs immediately following injection. Reactions may also
`include asthenia, back pain, bacterial infection, chills,
`cyst, face edema, fever, flu syndrome, infection, injection
`site erythema,
`injection site hemorrhage,
`injection site
`induration,
`injection site
`inflammation,
`injection site
`site pain,
`mass,
`injection site pruritus,
`
`15
`
`20
`
`25
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 12
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`

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`
`-12-
`
`injection site urticaria, injection site welt, neck pain,
`pain, migrane,
`syncope,
`tachycardia,
`vasodilatation,
`anorexia,
`diarrhea,
`gastroenteritis,
`gastrointestinal
`disorder, nausea, vomiting, ecchymosis, peripheral edema,
`arthralgia, agitation,
`anxiety,
`confusion,
`foot drop,
`hypertonia,
`nervousness,
`nystagmus,
`speech
`disorder,
`tremor,
`vertigo,
`bronchitis,
`dyspnea,
`laryngismus,
`rhinitis, erythema, herpes simplex, pruritus,
`rash, skin
`nodule,
`sweating, urticaria,
`ear pain,
`eye disorder,·
`dysrnenorrheal, urinary urgency, and vaginal moniliasis.
`
`5
`
`10
`
`As used herein, injection site reaction ( ISR) refers to a
`reaction
`such
`as. erythema,
`hemorrhage,
`induration,
`inflammation, mass, pain, pruritus, urticaria, and welt
`that occurs immediately around the site of injection.
`
`term Gd-enhancing lesions refers to
`the
`15 As used herein,
`lesions that result from a breakdown of the blood-brain
`barrier, which appear in contrast studies using gandoliniurn
`contrast
`agents.
`Gandolinium
`enhancement
`provides
`information as
`to the age of a
`lesion, as Gd-enhancing
`lesions typically occur within a six week period of lesion
`formation.
`
`20
`
`images refers to
`As used herein, the term Tl-weighted MRI
`an MR-image that emphasizes Tl contrast by which lesions
`may be visualized.
`Abnormal areas in a Tl-weigted MRI
`image are "hypointense" and appear as dark spots.
`These
`spots are generally older lesions.
`
`25
`
`As used herein, the term "unit dosage" refers to physically
`discrete units suited as single administration dose for a
`subject
`to be
`treated,
`containing
`a
`therapeutically
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 13
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`
`-13-
`
`effective quantity of active compound in association with
`the required pharmaceutical carrier, e.g., a syringe.
`
`the Examples section
`invention is illustrated in
`This
`5 which follows.
`This section is set forth to aid in an
`understanding of the invention but is not intended to, and
`should not be construed to, limit in any way the invention
`as set forth in the claims which follow thereafter.
`
`Examp.les
`
`10
`
`EXAMPLE 1. 9 MONTH 40 MG GLATIRAMER ACETATE TREATMENT
`
`Objectives:
`
`To evaluate the safety and efficacy of 40mg of glatiramer
`
`acetate treatment for 9 months, compared to Copaxone® (20
`formulation) both administered by daily subcutaneous
`mg
`injection, as reflected primarily by Gd-enhancing lesions
`on Tl-weighted MRI images, and by relapse rate.
`
`15
`
`Preparation of 40mg GA Injection:
`
`Quantitative Composition of Copaxone 40 mg/PFS Injection
`Name of Ingredient
`Unit Dose, mg/mL
`Glatiramer Acetate OS
`40 mg
`
`Mannitol
`
`Sterilized Water for
`Injection
`
`40 mg
`
`1.0 mL
`
`20
`
`Copaxone (Glatiramer Acetate Injection) 40 mg/PFS is a solution
`containing dose of 40 mg of the drug substance and 40 mg of
`Mannitol USP
`in
`1 mL
`sterilized water
`for
`injection.
`Compounding procedures
`including dissolving of Glatiramer
`
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`
`-14-
`
`(providing a final concentration of
`Acetate drug substance (OS)
`40 mg/mL .of anhydrous form} in water for injection with addition
`of 40 mg/mL Mannitol. The DS is the active substance only. The
`drug product (DP) is the mixture of carrier including the active
`substance.
`
`Design/Methods:
`
`least one Gd(cid:173)
`(90) eligible subjects with at
`Ninety
`enhancing lesion at screening
`(month -1) were randomized
`into 9-month, double-blind, parallel group study and
`received sc
`injection of either 40mg/d or 20mg/d GA.
`Subjects underwent MRI scans at months 3, 7, 8 and 9.
`Neurological examinations were performed in study centers
`at screening, baseline (month 0), and at months 3, 6, and
`9. Suspected relapses were confirmed by
`the examining
`neurologist within 7 days.
`
`5
`
`10
`
`15
`
`The primary efficacy endpoint·was the total number of Gd(cid:173)
`enhancing lesions on Tl-weighted
`images, as measured at
`months 7,
`and 9. The difference between
`the
`two
`8
`treatment arms was assessed using a Poisson regression
`20 model accounting for study-site, and baseline Gd-enhancing
`lesion counts.
`
`Results:
`
`In 90 RRMS patients, age ranges between 23.4-51.2 years
`(mean ± SE 37.2± 0.7). At entry, mean duration of disease
`25 was 3.5±0.5 years (range: 0 - 17.5 years), mean EDSS 2.0±
`0.1 (range: 0 - 4.5), and mean annual relapse rate (ARR)
`based on patients' entire history was 1.5 ± 0.1 (range: 1
`- 5). Mean Gd-enhancing lesions at screening was 3.4 ±0.34
`( n=8 9) .
`( Se·e Figure 1) The two groups were comparable in
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 15
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`PCT/US2007/000575
`
`-15-
`
`their MS demographic, clinical and MRI parameters at
`
`entry.
`
`95% CI 0.36-1.08,
`{RR=0.62,
`reduction
`38% greater
`A
`20 mg
`in
`the mean
`p=0.0898)
`in
`favor of 40 mg vs.
`cumulative number of Gd-enhancing lesions at month 7, 8
`and 9
`(mean±SD 0.79 ± 1.36 vs. 1.32±1.51 lesions p~r scan
`for the 40 and 20 mg groups, respectively) {See Figure 2
`and Table 1)
`was observed. This difference has emerged
`as early as 3 months { 1. 33± 1. 58
`lesions vs. 2. 61±4. 22
`lesions
`for
`the .40 and 20 mg groups,
`respectively,
`p=0.005).
`(See Figure 3 and Table 2}. The significance of
`the result at 3 months is shown in Figure 3. When compared
`to baseline, the risk of having enhancement at month 7, 8
`and 9 was
`reduced by 75%
`(RR 0.25, 95% CI 0.15-0.40,
`p<.0001)
`in the 40 mg/day and by 65%
`(RR 0.35, 95% CI
`0.24-0.53, p<.0001)
`in the 20 mg/day group. Mean relapse
`rate after 9 months reached 0.57 and 0.34 for the ·20mg and
`40 mg groups respectively, with a delay in time of 20%
`patients their first on trial relapse of 213 and 80 days
`for the 40 and 20 mg/day groups, respectively. (See Figure
`4 and Table 3) The safety profile of the 40 mg/d dose is
`essentially similar to the currently available 20 mg/day
`dose with a slight tendency of higher incidence of IPIR.
`
`Figure 6 shows the mean ± SE of new T2 lesions by month,
`from month 3 to month 9, of the 20 mg GA per day and 40 mg
`GA per day dosage groups. Figure 7 and Table 6 show the
`cumulative number of new T2 Gd-enhancing lesions at·months
`8 and 9
`in the 20 mg GA per day and 40 mg GA per day
`dosage groups.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 16
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`-16-
`
`Table 1. Primary Analysis:
`
`ITT Cohort
`
`( N=81) Cumulative
`
`Number of Tl Gd-Enhancing Lesions at Months 7, 8, and 9
`
`GA 20mg-Adjusted Means [95%CL)
`
`2.96 -
`
`[ 1. 90, 4.59]
`
`GA 40mg-Adjusted Means [95%CL)
`
`1.84 -
`
`[ 1. 11, 3. 05]
`
`RR (Relative Risk)
`
`[95%CL)
`
`0.62 -
`
`[0.36, 1.08]
`
`LR-Test-P value
`
`0.0898
`
`(See also Figure 2)
`
`5 Table 2. Post Hoc - Analysis: ITT (n=84) Cumulative Number
`of Tl Gd-Enhancing Lesions at Month 3
`
`GA 20mg-Adjusted Means [95%CL]
`
`0.72 -
`
`[0.47, 1.10)
`
`GA 40mg-Adjusted Means [95%CL]
`
`0.35 -
`
`[0.21, 0.58)
`
`RR (Relative Risk)
`
`[95%CL]
`
`0.48 -
`
`[0.29, 0.82)
`
`LR-Test-P value
`
`0.0051
`
`(See also Figure 3)
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 17
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`

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`
`Table 3. Number of Confirmed Relapses on Trial
`
`GA 20mg-Adjusted Means [95%CL]
`
`0.57 -
`
`(0.37, 0. 86]
`
`GA 40mg-Adj':1sted Means
`
`[95%CL]
`
`0.34 -
`
`[0.20, 0. 57)
`
`RR (Relative Risk)
`
`[95%CL]
`
`0.59 -
`
`[0.31, 1. 16]
`
`LR-Test-P value
`
`0.1202
`
`(See also Figure 4)
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 18
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`

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`-18-
`
`Table 4. Potential IPIR: Immediate Post Injection Reaction
`
`IGA 20mg (N=44)
`
`IGA 40mg (N=46)
`
`No.of
`No.of No.of %of
`Reports Subjects Subjects Reports
`
`L\
`
`No. of %of
`Subjects Subjects (%)
`
`Any symptom
`
`39
`
`Palpitations
`
`I
`
`10
`
`t
`
`22.7
`
`2.3
`
`52
`
`10
`
`Feeling Hot/
`Flushing I
`
`Hot Flush
`
`Tachycardia
`
`Dyspnoea
`
`Chest
`
`Discomfort/
`
`13
`
`6
`
`13.6
`
`16
`
`.
`
`10
`
`.
`
`6
`
`.
`
`13.6
`
`3
`
`17
`
`15
`
`5
`
`9
`
`2
`
`7
`
`32.6
`
`9.9
`
`10.9
`
`8.6
`
`19.5
`
`5.9
`
`4.3
`
`4.3
`
`15.2
`
`1.6
`
`Chest Pain/
`
`15
`
`6
`
`13.6
`
`6
`
`4
`
`8.7
`
`-4.9
`
`Non-Cardiac
`
`Chest Pain
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 19
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`

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`
`PCT/US2007/000575
`
`-19-
`
`Table 5. Injection Site Reactions
`
`GA 20mg (N=44}
`
`GA 40mg (N=4 6)
`
`No. of No. of
`% of
`% of
`No. of No. of
`Reports Subjects Subjects Reports Subjects Subjects
`
`113
`
`38
`
`86.4
`
`126
`
`39
`
`84.8
`
`No Injection Site Necrosis or Lipoatrophy
`
`Table 6. Cumulative Number of New T2 Gd-Enhancing Lesions
`at Months 8 and 9
`(N=81}
`
`5
`
`10
`
`GA 20mg-Adjusted Means [95%CL]
`
`1.04 -
`
`[0.58, 1. 8 6]
`
`GA 40mg-Adjusted Means [95%CL]
`
`0.73 -
`
`[0.40, 1.35]
`
`RR (Relative Risk}
`
`[95%CL]
`
`0.70 -
`
`[0.38, 1.30]
`
`LR-Test-P value
`
`0.2562
`
`(See also Figure 7)
`
`Conclusions:
`
`in
`increased efficacy observed with 40 mg/day GA
`The
`reducing MRI-measured disease activity and relapse rate
`indicates that it is well tolerated and can improve the
`treatment of RRMS patients. The
`improvement in efficacy,
`however, is not accompanied by a corresponding increase of
`adverse reactions which would be expected upon a doubling
`of the administered dose.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 20
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`

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`
`PCT/US2007/000575
`
`-20-
`
`the accelerated rate at which the 40
`Also observed was
`mg/day dose became effective as compared to the 20 mg/day
`dose. This was unexpected. Specifically, the 40 mg/day
`dose showed efficacy, as measured by MRI, by the third
`month, whereas the 20 mg/day dose did not show efficacy
`The results at
`three months
`the sixth month.
`until
`comparing the 40 mg/day dosage with the 20 mg/day dosage
`are shown in Figure 3 and Table 2 above.
`
`5
`
`A
`
`(1991)).
`
`IO
`
`25
`
`40 mg/day GA
`increased efficacy observed with
`The
`a
`in view of another
`administration was also unexpected
`finding that the administration of 15 mg twice per day (30
`produce
`statistically
`per
`day)
`of GA
`did not
`mg
`significant difference between
`the placebo and
`treated
`groups for the arrest or reversal of disease progress in
`15 patients affected by the chronic-progressive MS (Bornstein
`et al.,
`placebo-controlled,
`double-blinded,
`M.B.
`randomized,
`two-center, pilot trial of Cop 1
`in chronic
`progressive multiple
`sclerosis, Neurology
`41:533-539
`In
`this previous double-blinded,
`randomized,
`20 placebo-controlled trial of GA in chronic progressive MS
`patients, patients received 15 mg GA twice daily. Patients
`continued in the study until they had demonstrated either a
`over
`conf irrned worsening
`their baseline
`EDSS
`score
`maintained for at least 3 months or had completed 24 months
`of
`treatment. There was
`no statistically significant
`difference between the results of placebo groups from the
`results of patients that received 30 mg per day.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 21
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`

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`PCT/US2007/000575
`
`-21-
`
`What is claimed is:
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`a patient
`symptom of
`a
`A method of alleviating
`suffering from a relapsing form of multiple sclerosis
`which comprises periodically administering
`the
`to
`patient by subcutaneous injection a single dose of a
`pharmaceutical
`composition
`comprising
`40 mg
`of
`glatiramer acetate so as to thereby alleviate the
`symptom of the patient.
`
`· cla·im
`The method of
`administration is daily.
`
`1, wherein
`
`the periodic
`
`claim 1, wherein
`The method of
`administration is every other day.
`
`the periodic
`
`the
`any of claims 1-3, wherein
`The method of
`relapsing form of multiple sclerosis is relapsing(cid:173)
`remitting multiple sclerosis.
`
`The method of claims 1-4, wherein the symptom is the
`frequency of relapses.
`
`the
`any of claims 1-5, wherein
`The method of
`pharmaceutical composition
`is
`in
`the
`form of
`a
`sterile solution.
`
`The method of
`pharmaceutical
`mannitol.
`
`the
`any of claims 1-6, wherein
`composition
`further
`comprises
`
`the
`any of claims 1-7, wherein
`The method of
`pharmaceutical composition has a pH in the range of
`5.5 to 8.5.
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 22
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`

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`
`-22-
`
`9.
`
`the pharmaceutical
`The method of claim 8, wherein
`composition has a pH in the range of 5.5 to 7.0.
`
`the
`any of claims 1-9, wherein
`10. The method of
`pharmaceutical composition is in a prefilled syringe
`and is self-administered by the patient.
`
`5
`
`IO
`
`15
`
`20
`
`11. A method of reducing MRI-monitored disease activity
`and burden of
`a patient suffering
`from multiple
`sclerosis which comprises periodically administering
`to
`the patient by subcutaneous
`injection a single
`dose of a pharmaceutical composition comprising 40 mg
`of glatiramer acetate.
`
`reducing MRI-
`12. The method of claim 11, wherein
`monitored disease activity and burden is reducing the
`mean cumulative number of Gd-enhancing lesions in the
`brain of the patient.
`
`reducing MRI-
`13. The method of claim 11, wherein
`monitored disease activity and burden is reducing the
`mean number of new T2
`lesions in the brain of the
`patient.
`
`14. The method of any of claims 11-13, wherein
`the
`periodic administration to the patient of the single
`dose of a pharmaceutical composition comprising 40 mg
`of glatiramer acetate further reduces a
`symptom of
`MS.
`
`25
`
`15. The method of claim 14, wherein the symptom is the
`frequency of relapses.
`
`16. A
`pharmaceutical
`injectable
`form
`
`composition
`comprising
`40
`
`in
`mg
`
`a
`
`dosage
`unit
`of glatiramer
`
`MYLAN PHARMS. INC. EXHIBIT 1004 PAGE 23
`
`

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`
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`
`-23-
`
`acetate and a pharmaceutically acceptable carrier.
`
`17. The pharmaceutical composition of claim 16, wherein
`
`the pharmaceutical composition is in the form of a
`sterile solution.
`
`5
`
`18. The pharmaceutical composition of claim 16 or 13,
`wherein
`the pharmaceutically acceptable carrier is
`rnannitol.
`
`19. The pharmaceutical composition of any of claims 16-18
`having a pH in the range of 5.5 to 8.5.
`
`10
`
`20. The pharmaceutical composition of claim 19 having a
`pH in the range of 5.5 to 7.0.
`
`21. The pharmaceutical composition of claims 16-20 in a
`prefilled syringe.
`
`15
`
`22. Use of glatiramer acetate in the manufacture of a
`pharmaceutical
`composition
`comprising
`a
`40 mg
`glatiramer acetate for subcutaneous administration to
`alleviate a symptom of a relapsing form of multiple
`sclerosis in a human patient.
`
`20
`
`23. The use
`of claim 22, wherein the relapsing form of
`multiple
`sc