(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization ‘/77’ I I53I4: .
`International Bureau
`
` (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, FI,
`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-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`(43) International Publication Date
`19 July 2007 (19.07.2007)
`
`(51) International Patent Claslflcatlonz
`A61K 38/16 (2006.01)
`
`(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:
`60/758,580
`
`11 January 2006 (11.01.2006) US
`
`(71) Applicant (for all designated States except BB, US):
`TEVA PHARMACEUTICAL INDUSTRIES, LTD.
`[IL/IL]; 5 Base] Street, P.O. BOX 3 [90, 49131 Petach-Tikva
`(IL)-
`
`(7l) Applicant (forBB only): TEVA PHARMACEUTICALS
`USA, INC. [US/US]; 1090 Horsham Road, North Wales,
`Pennsylvania 19454 (US).
`
`(72) Inventor: PINCHASI, Irlt; 43 Brandeis Street, Ra'anana
`(IL).
`
`(74) Agent: WHITE, John, E; Cooper & Dunham LLP, 1185
`Avenue of the Americas, New York, NY 10036 (US).
`
`(54) Title: METHOD OF TREATING MULTIPLE SCLEROSIS
`
`
`
`007/081975A2I||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`6. (57) Abstract: This invention provides a method of alleviating a symptom of a patient sufiering 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. This invention also
`provides a method of reducing Gd-enhancing lesions in the brain and a pharmaceutical composition in a unit dosage.
`
`W0
`
`AMNEAL EXHIBIT NO. 1005 Page 1
`
` AMNEAL
`
`

`
`WO 2007/081975
`
`PCTfUS2007/000575
`
`METHOD OF TREATING MULTIPLE SCLEROSIS
`
`Throughout
`
`this
`
`application
`
`various
`
`publications
`
`are
`
`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.
`
`I0
`
`Backggound or The Invention
`
`one of
`
`the more
`
`common chronic neurologic diseases
`
`in
`
`human adults ‘is multiple
`
`sclerosis
`
`(“MS”).
`
`MS
`
`is a
`
`chronic,
`
`inflammatory
`
`CNS
`
`disease
`
`characterized
`
`been
`also
`has
`MS
`demyelination.
`by
`pathologically
`classified as an autoimune disease. MS disease activity
`
`15
`
`can be monitored by magnetic resonance imaging (MRI) of
`
`the brain, accumulation of disability,
`
`as well as rate and‘
`
`severity of relapses.
`
`There are five main forms of multiple sclerosis: 1) benign
`
`20
`
`multiple
`
`sclerosis;
`
`2)
`
`relapsing—remitting multiple
`
`sclerosis
`
`(RRMS):
`
`3)
`
`secondary
`
`progressive multiple
`
`sclerosis
`
`(SPMS);
`
`4)
`
`primary
`
`progressive multiple
`
`sclerosis
`
`(PPMS);
`
`and 5) progressive-relapsing multiple
`
`sclerosis
`
`(PRMS)
`
`(What
`
`are
`
`the
`
`Types
`
`of Multiple
`
`25
`
`Sclerosis?,
`
`2005
`
`<http://imaginis.com/multiple-
`
`sclerosis/types-of-ms.asp? mode=1>).
`
`Chronic progressive
`
`multiple sclerosis is a term used to collectively-refer to
`
`SPMS,
`
`PPMS,
`
`and PRMS
`
`(Types of bhdtiple Sclerosis
`
`(MS),
`
`2005 <http://www.themcfox.com/multiple-sclerosis/types-of-
`
`30
`
`ms/
`
`types-of-multiple-sclerosis.htm>).
`
`The
`
`relapsing
`
`AMNEAL EXHIBIT NO. 1005 Page2
`
` AMNEAL
`
`

`
`W0 2007/081975
`
`PCT/US2007/000575
`
`-2-
`
`forms of multiple sclerosis are SPMS with superimposed
`
`relapses, RRMS and PRMS.
`
`Benign multiple sclerosis
`
`is a
`
`retrospective diagnosis
`
`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
`
`multiple
`
`sclerosis.
`
`Patients
`
`suffering
`
`from
`
`of
`
`RRMS
`
`experience sporadic exacerbations or relapses,
`
`as well as
`
`I0
`
`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
`
`15
`
`neurological
`
`deficits
`
`than
`
`RRMS
`
`patients.
`
`Enlarged
`
`ventricles,
`
`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
`
`25'
`
`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>).
`
`Glatiramer acetate (GA),
`
`a mixture of polypeptides which
`
`30
`
`do not all have the same amino acid sequence,
`
`is marketed
`
`under
`
`the tradename Copaxone®. GA comprises
`
`the acetate
`
`AMNEAL EXHIBIT NO. 1005 Page3
`
` AMNEAL
`
`

`
`W0 2007/081975
`
`PCT/US2007/000575
`
`_3_
`
`salts of polypeptides
`
`containing L-glutamic
`
`acid,
`
`L-
`
`alanine,
`
`L-tyrosine
`
`and L-lysine
`
`at
`
`average molar
`
`fractions of 0.141, 0.427, 0.095 and 0.338,
`
`respectively,
`
`The average molecular weight of Copaxone® is between 5,000
`
`5
`
`and
`
`9,000
`
`daltons.
`
`(“Copaxone”,
`
`Physician's
`
`Desk
`
`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:
`
`10
`
`.
`
`.
`
`(Glu, Ala, Lys, Tyr)x°xCH3COOH
`‘
`(C5H9N04 ‘ C3H7N02 ' C651-«N202 ' C9H11N03) X ° xC2H¢02
`CAS - 147245-92-9
`
`(“Copaxone”, Physician's Desk Reference,
`
`(2000), Medical
`
`Economics Co., Inc.,
`
`(Montvale, NJ), 3115.)
`
`Copaxone® (20
`
`15
`
`mg glatiramer acetate injection)
`
`is an. approved ‘therapy
`
`for patients with relapsing remitting multiple sclerosis
`
`(RRMS).
`
`Glatiramer acetate has also been disclosed for use in the
`
`treatment
`
`of
`
`other
`
`autoimmune diseases
`
`(U.S.
`
`Patent
`
`20
`
`Publication No.
`
`2002/0055466 A1
`
`(R. Aharoni et al.),
`
`inflammatory
`
`non—autoimmune
`
`diseases
`
`(U.S.
`
`Patent
`
`(V. Wee Yong et a1.); and
`Publication No. 2005/0014694 A1
`u.s. Patent Application No.‘ 2oo2/0077273 A1, published
`
`_ June .20,
`
`2002
`
`(Young‘ et al.))
`
`and other- diseases
`
`(U.S.
`
`25
`
`Patent Publication Nos. 2003/0004099 A1 and 2002/0037848
`
`A1
`
`(Eisenbach-Schwartz, et al.); U.S. Patent No. 6,514,938
`
`2003
`4,
`February
`issued
`B1,
`International Publication No.
`
`wo
`
`et
`(Gad
`01/60392,
`
`PCT
`a1.);
`published
`
`August
`
`23,
`
`2001
`
`(Gilbert
`
`et a1.);
`
`PCT
`
`International
`
`30
`
`Publication No. W0 O0/27417,
`
`published May
`
`19,
`
`2000
`
`AMNEAL EXHIBIT NO. 1005 Page4
`
` AMNEAL
`
`

`
`W0 2007/081975
`
`PCT/US2007/000575
`
`-4...
`
`(Aharoni et a1.); and PCT International Publication No. WO
`
`01/97846, published December 27, 2001 (Moses et al.)).
`
`The 20mg/day subcutaneous dose has been shown to reduce
`
`the total number of enhancing lesions in MS patients as
`
`5 measured
`
`by MRI
`
`(G.
`
`Comi
`
`et al.,
`
`European/Canadian
`
`Multicenter, Double—B1ind, 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.
`
`10
`
`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
`
`have
`
`a
`
`corresponding
`
`increase
`
`in'
`
`adverse
`
`reactions
`
`experienced by the patient.
`
`AMNEAL EXHIBIT NO. 1005 Page 5
`
` AMNEAL
`
`

`
`WO 2007/081975
`
`PCTfUS2007/000575
`
`Sgggggz of the Invention
`
`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
`
`S
`
`the patient by subcutaneous injection a single dose of a
`
`pharmaceutical composition comprising 40 mg of glatiramer
`
`acetate so as
`
`to thereby alleviate the symptonl of
`
`the
`
`patient.
`
`This
`
`inventions also ‘provides a method of
`
`reducing MRI-
`
`10
`
`monitored disease activity and
`
`burden
`
`ofk a patient
`
`suffering
`
`from
`
`multiple
`
`sclerosis
`
`which
`
`comprises
`
`periodically administering to the patient by subcutaneous
`
`a pharmaceutical composition
`injection a single» dose of
`comprising 40 mg of glatiramer acetate.
`
`I5
`
`This
`
`invention
`
`further
`
`provides
`
`a
`
`pharmaceutical
`
`‘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
`
`20
`
`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.
`
`AMNEAL EXHIBIT NO. 1005 Page6
`
` AMNEAL
`
`

`
`WO 2007/081975
`
`PCTfUS2007/000575
`
`-5-
`
`Brief Description of the riflree
`
`Figure 1. Mean :I: SE Of T1 Gd-Enhancing Lesions by Month -
`Mean t SE of T1 Gd-enhancing lesions by month comparing 2!-)
`
`mg and 40 mg per day GA dosages.
`
`Figure 2.
`
`Primary Analysis:
`
`I'I."1' Cohort
`
`(N=81)
`
`Cumulative
`
`Number of T1-Enhancing Lesions at Months 7,
`
`8
`
`and 9
`
`-
`
`primary analysis of the cumulative number of T1 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) .
`
`-
`
`I0
`
`Figure 3. Post Hoc Analysis:
`
`ITT (N=84)
`
`Cumulative Number
`
`of T1 GD-Enhancing Lesions at Month 3 -
`
`Post—hoc analysis
`
`of the cumulative number of T1-enhanceing lesions at month
`
`3
`for
`ITT (n=84)
`dosages.
`
`comparing 20 mg and 40 mg per day GA
`.
`
`IS
`
`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.
`
`Figure 5.
`
`Time
`
`to First Confirmed Relapse
`
`- Graphic
`
`20
`
`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 t SE: of New T2 Lesions by Month - A graphic
`
`comparison of the mean t SE new lesions by month between
`
`the 20 mg GA per day and the 40 mg GA per day dosage
`
`25
`
`groups.
`
`Figure 7. Cumulative Number of New T2 Gd—Enhancing Lesions
`
`at Months
`
`8 and 9
`
`(N=81)
`
`" a graphic comparison of
`
`the
`
`AMNEAL EXHIBIT NO. 1005 Page7
`
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`
`

`
`WO 2007/081975
`
`PCTfUS2007/000575
`
`-7-
`
`adjusted means of
`
`the cumulative number of
`
`new T2 Gd-
`
`enhancing lesions at months
`
`8 and 9 between the 20 mg GA
`
`per day and 40 mg GA per day dosage groups.
`
`AMNEAL EXHIBIT NO. 1005 Page8
`
` AMNEAL
`
`

`
`WO 2007/081975
`
`PCTfUS2007/000575
`
`-3-
`
`Detailed Description of the Invention
`
`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
`
`5
`
`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.
`
`In an embodiment,
`
`the periodic administration is daily:
`
`10
`
`In another
`
`embodiment,
`
`the periodic administration is
`
`every other day.
`
`the relapsing form of multiple
`In yet another embodiment,
`sclerosis is relapsing—remitting multiple sclerosis.
`
`In a further embodiment,
`
`the symptom is the frequency of
`
`IS
`
`relapses.
`
`In an embodiment,
`
`the pharmaceutical composition is in the
`
`form of a sterile solution.
`
`In’ another
`
`embodiment,
`
`the pharmaceutical
`
`composition
`
`further comprises mannitol.
`
`20
`
`In yet another embodiment,
`
`the pharmaceutical composition
`
`has a pH in the range of 5.5 to 8.5.
`
`In an embodiment,
`
`the
`
`pharmaceutical composition has a pH in the range of 5.5 to
`7.0.
`
`In a further embodiment,
`
`the pharmaceutical composition is
`
`25
`
`in a prefilled syringe and is self-administered by the
`
`patient.
`
`AMNEAL EXHIBIT NO. 1005 Page9
`
` AMNEAL
`
`

`
`W0 2007/081975
`
`PCT/US2007/000575
`
`-9-
`
`This
`
`invention also provides 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
`
`5
`
`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 mean cumulative number of Gd-
`
`enhancing lesions in the brain of the patient.
`
`lb
`
`In
`
`another
`
`embodiment,
`
`reducing MRI—monitored disease
`
`activity and burden is reducing the mean number of new T2
`
`lesions in the brain of the patient.
`
`In any of
`
`the above
`
`embodiments of
`
`the method,
`
`the
`
`periodic administration to the patient of the single dose
`
`I5
`
`of
`
`a
`
`.pharmaceutical
`
`composition comprising
`
`40 mg of
`
`glatiramer acetate further reduces a symptom of MS.
`
`In an
`
`embodiment,
`
`the symptom may be the frequency of relapses.
`
`20
`
`25
`
`In any embodiment of a nethod of
`
`reducing MRI-monitored
`
`disease activity and burden,
`the periodic administration
`is daily; The periodic administration may alternatively be
`every other day.
`'
`
`In further
`
`embodiments of
`
`the method,
`
`the patient
`
`is
`
`In
`suffering from a relapsing form of multiple sclerosis.
`an embodiment,
`the relapsing form of multiple sclerosis is
`relapsing—remitting multiple sclerosis.
`
`In further embodiments of the nmthod,
`
`the pharmaceutical
`
`composition is in the form of a sterile solution.
`
`In
`
`yet
`
`further
`
`embodiments
`
`of
`
`the method,
`
`the
`
`AMNEAL EXHIBIT NO. 1005 Page 10
`
` AMNEAL
`
`

`
`W0 2007/081975
`
`PCT/US2007/000575
`
`-10..
`
`pharmaceutical composition further comprises mannitol.
`
`In further embodiments of
`
`the method,
`
`the pharmaceutical
`
`composition 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
`composition
`is
`in a prefilled syringe
`and
`is
`self-
`
`administered by the patient.
`
`This
`
`invention
`
`further
`
`provides
`
`a
`
`pharmaceutical'
`
`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.
`
`embodiment,
`In another
`carrier is mannitol.
`
`the pharmaceutically acceptable
`
`10
`
`15
`
`In yet another embodiment,
`
`the pharmaceutical composition
`
`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.
`
`20
`
`hi a further embodiment,
`
`the pharmaceutical compositions
`
`is in a prefilled syringe.
`
`This invention also provides a use of glatiramer acetate
`
`in
`
`the manufacture
`
`of
`
`a
`
`pharmaceutical
`
`composition
`
`25
`
`comprising a
`
`40 mg glatiramer acetate for
`
`subcutaneous
`
`administration to alleviate a symptom of a relapsing form
`
`of multiple sclerosis in a human patient.
`
`AMNEAL EXHIBIT NO. 1005 Page 11
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`
`-11-
`
`In an
`
`embodiment of
`
`the use,
`
`the
`
`relapsing form of
`
`multiple
`
`sclerosis
`
`is
`
`relapsing-remitting multiple
`
`sclerosis.
`
`In another
`
`embodiment of
`
`the use,
`
`the symptom is the
`
`frequency of relapses.
`
`In a
`
`further embodiment of
`
`the use,
`
`the‘ pharmaceutical
`
`composition is in the form of a sterile solution for once
`
`daily administration.
`
`In
`
`an
`
`embodiment '"of
`
`the
`
`1136,
`
`the
`
`pharmaceutical-~»
`
`10
`
`composition further comprises mannitol.
`
`In another
`
`embodiment of
`
`the use,
`
`the pharmaceutical
`
`composition is in the form of a sterile solution having a
`
`pH in
`
`the
`
`range
`
`5.5 to 8.5.
`
`In an
`
`embodiment,
`
`the
`
`pharmaceutical composition is the in the form of a sterile
`
`15
`
`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
`
`20
`
`25
`
`As used herein,
`
`immediate post
`
`injection reaction (IRPR)
`
`refers to ea
`
`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,
`induration,
`injection site inflamation,
`
`injection site
`injection site
`
`mass,
`
`injeption
`
`site
`
`pain,
`
`injection
`
`site pruritus,
`
`AMNEAL EXHIBIT NO. 1005 Page 12
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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,
`
`5
`
`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,
`dysmenorrheal, urinary urgency, and vaginal moniliasis.
`
`10
`
`As used herein,
`
`injection site reaction (ISR)
`
`refers to a
`
`reaction
`
`such
`
`as.
`
`erythema,
`
`hemorrhage,
`
`induration,
`
`inflamation, mass, pain, pruritus, urticaria,
`
`and welt
`
`that occurs immediately around the site of injection.
`
`15
`
`As used herein,
`
`the term Gd-enhancing lesions refers to
`
`lesions that
`
`result
`
`from a breakdown of
`
`the blood-brain
`
`barrier, which appear in contrast studies using gandolinium
`
`contrast
`
`agents .
`
`Gandolinium
`
`enhancement
`
`provides
`
`information as
`
`to the age of
`
`a
`
`lesion,
`
`as Gd-enhancing
`
`20
`
`lesions typically occur within a six week period of lesion
`
`formation .
`
`As used herein,
`
`the term T1—weighted MRI
`
`images refers to
`
`an MR-image
`
`that emphasizes T1 contrast by which lesions
`
`may be visualized.
`
`Abnormal areas
`
`in a Tl—weigted MRI
`
`25
`
`image are “hypointense” and appear as dark spots.
`
`These
`
`spots are generally older lesions.
`
`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 ‘
`
`AMNEAL EXHIBIT NO. 1005 Page 13
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`
`-13-
`
`effective quantity of active compound in association with
`
`the required pharmaceutical carrier, e.g., a syringe.
`
`This
`
`invention is illustrated in the Examples
`
`section
`
`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.
`
`3335193
`
`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®>(2O
`
`mg
`
`formulation) both administered by daily subcutaneous
`
`15
`
`injection, as reflected primarily by Gd-enhancing lesions
`
`on T1—weighted MRI images, and by relapse rate.
`
`Preparation of 40mg GA Injection:
`
`Quantitative Composition of Copaxone 40 mg/PFS Injection
`
`Name of Ingredient
`
`Unit Dose, mg/mL
`
`Glatiramer Acetate DS
`
`_
`
`Mannitol
`
`sterilized Water for
`Injection
`
`40 mg
`
`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.
`
`C°mP°Undin9
`
`procedures
`
`including
`
`dissolving
`
`of Glatiramer
`
`AMNEAL EXHIBIT NO. 1005 Page 14
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`
`-14-
`
`Acetate drug substance (DS)
`
`(providing a final concentration of
`
`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
`substance.
`
`(DP)
`
`is the mixture of carrier including the active
`
`Design/Methods:
`
`I0
`
`15
`
`20
`
`25
`
`Ninety
`
`(90)
`
`eligible subjects with at
`
`least
`
`one Gd-
`
`enhancing lesion at screening (month -1) were randomized
`
`into 9-month,
`
`double-blind, parallel
`
`group
`
`study and
`
`received so 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.
`
`The primary efficacy endpoint-was the total number of Gd-
`
`enhancing lesions on T1—weighted images, as measured at
`
`months
`
`7,
`
`8
`
`and
`
`9.
`
`The
`
`difference
`
`between
`
`the
`
`‘CWO
`
`treatment
`
`arms was assessed using a Poisson regression
`
`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 t SE 37.21 0.7).
`
`At entry, mean duration of disease
`
`was 3.5iO.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 t 0.1
`
`(range:
`
`1
`
`- 5). Mean Gd—enhancing lesions at screening was 3.4 $0.34
`
`(n=39)-
`
`(See Figure 1) The two groups were comparable in
`
`AMNEAL EXHIBIT NO. 1005 Page 15
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`
`... 1 5 ..
`
`their MS demographic, clinical
`
`and MRI parameters at
`
`entry.
`
`A
`
`38% greater
`
`reduction
`
`(RR=0.62,
`
`95% CI 0.36-1.08,
`
`p=0.0898)
`
`in favor of
`
`40 mg vs.
`
`20 mg
`
`in the mean
`
`cumulative number of Gd—enhancing lesions at nmnth 7,
`
`8
`
`and 9
`
`(meaniSD 0.79 i 1.36 vs.
`
`1.32i1.51 lesions per 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. 2.61t4.22
`
`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<.O001)
`
`in the 40 mg/day and by 65% (RR 0.35,
`
`95% CI
`
`0.24-0.53, p<.O001)
`
`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 1 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.
`
`l0
`
`15
`
`20
`
`25
`
`30
`
`AMNEAL EXHIBIT NO. 1005 Page 16
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`-15-
`
`Table 1. Primary Analysis:
`
`ITT Cohort
`
`(N=81) Cumulative
`
`Number of T1 Gd-Enhancing Lesions at Months 7, 8, and 9
`
`
`
`
`
`
`
`
`
`
`(See also Figure 2)
`
`5 Table 2. Post Hoc - Analysis:
`
`I'I"1‘
`
`(n=84) Cumulative Number
`
`of T1 Gd-Enhancing Lesions at Month 3
`
`
`
`
`
`(See also Figure 3)
`
`
`
`
`
`
`AMNEAL EXHIBIT NO. 1005 Page 17
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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-Adjgsted Means
`
`[95%CL]
`
`0.34 — [0.20, 0.57]
`
`‘LR-Test—P value
`
`RR (Relative Risk)
`
`[95%CL]
`
`0.59 - [0.31, 1.16]
`
`(See also Figure 4)
`
`AMNEAL EXHIBIT NO. 1005 Page 18
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`
`-18..
`
`Table 4. Potential IPIR:
`
`Immediate Post‘ Injection Reaction
`
`A20mg(N=44)
`
`A40mg(N=46)
`
`
`
`
`°I
`
`
`
`
`
`No. of No. of
`
`- % of
`
`No. of
`
`No. of
`
`% of
`
`Reports Subjects Subjects Reports
`
`Subjects Subjects
`
`(%)
`
`22.7
`
`Feeling Hot!
`
`Flushing /
`
`Hot Flush
`
`Discomfortl
`
`Chest Pain/
`
`
`
`Non-Cardiac
`
`AMNEAL EXHIBIT NO. 1005 Page 19
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`-19-
`
`Table 5. Injection Site Reactions
`
`GA 20mg (N=44)
`
`GA 40mg (N=46)
`
`No. of
`
`No. of
`
`% of
`
`No. of No. of
`
`% of
`
`Reports Subjects Subjects Reports Subjects Subjects
`
`
`
`No Injection Site Necrosis or Lipoatrophy
`
`
`
`
`Table 6. Cumulative Number of New T2 Gd-Enhancing Lesions
`
`at Months 8 and 9 (N=81)
`
`
`
`
`
`(See also Figure 7)
`
`Conclusions:
`
`
`
`
`
`
`
`
`
`
`The
`
`increased efficacy observed with 40‘ mg/day GA in
`
`reducing MRI-measured disease activity and relapse rate
`
`10
`
`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.
`
`AMNEAL EXHIBIT NO. 1005 Page 20
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`
`-20-
`
`Also observed was
`
`the accelerated rate at which the 40
`
`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
`until
`the
`sixth month.
`The
`results at
`
`show efficacy
`three months
`
`comparing the 40 mg/day dosage with the 20 mg/day dosage
`
`are shown in Figure 3 and Table 2 above.
`
`I0
`
`15
`
`20
`
`25
`
`The
`
`increased efficacy observed with a
`administration was
`
`also unexpected
`
`in view of another ..
`
`40 mg/day GA
`
`finding that the administration of 15 mg twice per day (30
`mg
`of
`‘GA
`did
`
`statistically
`produce
`not
`day)
`per
`significant difference between the placebo and treated
`
`groups for the arrest or reversal of disease progress in
`
`patients affected by the chronic-progressive MS
`
`(Bornstein
`
`M.B.
`
`et
`
`al.,
`
`A
`
`placebo—controlled,
`
`double-blinded,
`
`randomized,
`
`two-center, pilot trial of Cop 1. ha chronic
`
`4l:533—539
`Neurology
`progressive multiple
`randomized,
`double—b1inded,
`(1991)).
`In
`this
`previous
`placebo-controlled trial of GA in chronic progressive MS
`
`sclerosis,
`
`patients, patients received 15 mg GA twice daily. Patients
`
`continued in the study until they had demonstrated either a
`
`confirmed worsening
`
`over
`
`their
`
`baseline
`
`EDSS
`
`SCOIG
`
`maintained for at least 3 months or had completed 24 months
`of
`
`There was
`
`no
`
`statistically significant
`
`treatment.
`
`difference between the results of placebo groups from the
`
`results of patients that received 30 mg per day.
`
`AMNEAL EXHIBIT NO. 1005 Page 21
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`
`-21-
`
`What is claimed is:
`
`1.
`
`A method of alleviating a
`
`symptom of
`
`a patient
`
`suffering from a relapsing form of multiple sclerosis
`
`which comprises periodically administering to the
`
`5
`
`patient by subcutaneous injection a single dose of a
`
`composition
`pharmaceutical
`glatiramer. acetate so as
`
`of
`mg
`40
`comprising
`to thereby alleviate the
`
`symptom of the patient.
`
`2.
`
`The method
`
`of
`
`-claim 1, wherein
`
`the ’ periodic
`
`10
`
`administration is daily.
`
`3.
`
`The method
`
`of
`
`claim 1, wherein
`
`the
`
`periodic
`
`administration is every other day.
`
`4.
`
`The method
`
`of
`
`any of_ claims
`
`1-3, wherein
`
`the
`
`relapsing form of multiple sclerosis is relapsing-
`
`15
`
`remitting multiple sclerosis.
`
`5.
`
`The method of claims 1-4, wherein the symptom is the
`
`frequency of relapses.
`
`6.
`
`The method of
`
`any of
`
`claims
`
`1-5, wherein
`
`the
`
`pharmaceutical
`
`composition
`
`is
`
`in the
`
`form of
`
`a
`
`20
`
`sterile solution.
`
`7.
`
`The method
`
`of
`
`any
`
`of
`
`claims
`
`1-6, wherein
`
`the
`
`pharmaceutical
`
`composition
`
`further
`
`comprises
`
`mannitol.
`
`8.
`
`The method of
`
`any
`
`of
`
`claims
`
`1-7, wherein
`
`the
`
`25
`
`pharmaceutical composition has a pH in the range of
`
`5.5 to 8.5.
`
`AMNEAL EXHIBIT NO. 1005 Page 22
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`
`-22-.
`
`9.
`
`The method of claim 8, wherein the pharmaceutical
`
`rcomposition has a pH in the range of 5.5 to 7.0.
`
`10.
`
`The method of
`
`any of
`
`claims
`
`1-9, wherein
`
`the
`
`pharmaceutical composition is in a prefilled syringe
`
`5
`
`and is self-administered by the patient.
`
`11.
`
`.A method of
`
`reducing MRI~monitored disease activity
`
`and burden of
`
`a patient
`
`suffering from multiple
`
`sclerosis which comprises periodically administering
`
`10
`
`'
`
`to the patient by subcutaneous
`injection a single
`dose of a pharmaceutical composition comprising 40 mg
`
`of glatiramer acetate.
`
`12.
`
`The method
`
`of
`
`claim 11, wherein
`
`reducing MRI-
`
`monitored disease activity and burden is reducing the
`
`mean cumulative number of Gd-enhancing lesions in the
`
`15
`
`brain of the patient.
`
`13.
`
`The method
`
`of
`
`claim 11, wherein
`
`reducing MRI-
`
`monitored disease activity and burden is reducing the
`
`mean number of new T2
`
`lesions in the brain of
`
`the
`
`patient.
`
`20
`
`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
`
`composition
`
`in
`
`a
`
`unit
`
`dosage
`
`injectable
`
`form comprising
`
`40 mg of glatiramer
`
`AMNEAL EXHIBIT NO. 1005 Page 23
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`
`PCTfUS2007/000575
`
`-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
`
`mannitol.
`
`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.
`
`22. Use of glatiramer acetate in the manufacture of a
`
`15
`
`pharmaceutical
`
`composition
`
`comprising
`
`a
`
`40
`
`mg
`
`glatiramer acetate for subcutaneous administration to
`
`alleviate a symptmn of a relapsing form of multiple
`
`sclerosis in a human patient.
`
`23.
`
`The use of claim 22, wherein the relapsing form of
`
`20
`
`multiple sclerosis
`
`is relapsing—remitting multiple
`
`sclerosis.
`
`24.
`
`The use of claim 22 or 23, wherein the symptom is the
`
`frequency of relapses.
`
`25.
`
`The
`
`use
`
`of
`
`any
`
`of
`
`claims
`
`22-24, wherein
`
`the
`
`25
`
`pharmaceutical
`
`composition
`
`is
`
`in the
`
`form of
`
`a
`
`sterile solution for once daily administration.
`
`AMNEAL EXHIBIT NO. 1005 Page 24
`
` AMNEAL
`
`

`
`W0 2007/081975
`
`PCT/US2007/000575
`
`-24-
`
`26.
`
`The
`
`use
`
`of
`
`any
`
`of
`
`claims
`
`22-25, wherein
`
`the
`
`pharmaceutical
`
`composition
`
`further
`
`Comprises
`
`mannitol.
`
`27.
`
`The
`
`use
`
`of
`
`any
`
`of
`
`claims
`
`22-26, wherein
`
`the
`
`pharmaceutical
`
`composition
`
`is
`
`in the
`
`form of
`
`a
`
`sterile solution having a pH in the range 5.5 to 8.5.
`
`28.
`
`The use of
`
`claim 27, wherein the pharmaceutical
`