`
`Exhibit 1013
`
`U.S. Patent Application Publication No.
`2010/0035850 A1 (“Meyeroff”)
`
`

`
`(19) United States
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0035850 A1
`(12) Patent Application Publication (10) Pub. No.: US 2010/0035850 A1
`Feb. 11, 2010
`Karlstadt Meyeroff et al.
`(43) Pub. Date:
`(43) Pub. Date:
`Feb. 11, 2010
`Karlstadt Meyeroff et al.
`
`US 20l00035850A1
`US 20100035850A1
`
`(54) METHOD OF TREATMENT FOR
`(54) METHOD OF TREATMENT FOR
`INFLAMMATORY BOWEL DISEASE
`INFLAMMATORY BOWEL DISEASE
`
`(75)
`Inventors:
`(75) Inventors:
`
`Robyn Gail Karlstadt Meyeroff,
`Robyn Gail Karlstadt Meyeroff,
`Cherry Hill, NJ (US); Ronald
`Cherry Hill, NJ (US); Ronald
`joseph Diebold, Chalfont, PA (US);
`joseph Diebold, Chalfont, PA (US);
`David Montague Pierce,
`David Montague Pierce,
`Bedfordshire (GB); Patrick T.
`Bedfordshire (GB); Patrick T.
`Martin, Gwynedd Valley, PA (US)
`Martin, GWynedd Valley, PA (US)
`
`Correspondence Address:
`Correspondence Address:
`DARBY & DARBY P.C.
`DARBY & DARBY P.C.
`P.O. BOX 770, Church Street Station
`P.O. BOX 770, Church Street Station
`New York, NY 10008-0770 (US)
`New York, NY 10008-0770 (US)
`
`(73) Assignee:
`(73) Assignee:
`
`Shire Development Inc., Wayne,
`Shire Development Inc., Wayne,
`PA (US)
`PA (US)
`
`(21) App1.No.:
`(21) Appl. No.:
`
`12/514,183
`12/514,183
`
`(22) PCT Filed:
`(22) PCT Filed:
`
`Sep. 27, 2007
`Sep. 27, 2007
`
`(86) PCT No.:
`(86)
`PCT No.:
`
`PCT/US07/79739
`PCT/US07/79739
`
`§ 371 (OX1),
`§ 371 (0X1)’
`Jun. 17, 2009
`(2), (4) Date:
`Jun. 17, 2009
`(2), (4) Date:
`Related U.S. Application Data
`Related US. Application Data
`
`(60) Provisional application No. 60/866,401, filed on Nov.
`(60)
`Provisional application No. 60/866,401, ?led on Nov.
`17, 2006.
`17, 2006.
`Publication Classification
`Publication Classi?cation
`
`(51)
`(51)
`
`Int. Cl.
`Int. Cl.
`(2006.01)
`A61K 31/606
`(2006.01)
`A61K 31/606
`(2006.01)
`A61P 1/04
`(2006.01)
`A61P 1/04
`(2006.01)
`A61P 1/06
`(2006.01)
`A61P 1/06
`(52) U.S. Cl. ...................................................... .. 514/166
`(52)
`US. Cl. ...................................................... .. 514/166
`(57)
`ABSTRACT
`(57)
`ABSTRACT
`The present invention provides methods of treating inflam-
`The present invention provides methods of treating in?am
`matory bowel disease comprising administering to a subject
`matory boWel disease comprising administering to a subject
`in which remission has not been achieved after a first treat-
`in Which remission has not been achieved after a ?rst treat
`ment of about 4-8 weeks of 5-ASA (mesalamine or 5-ASA),
`ment of about 4-8 Weeks of S-ASA (mesalamine or S-ASA),
`a further daily dose greater than about 4 g of 5-ASA in
`a further daily dose greater than about 4 g of S-ASA in
`controlled release form to achieve a favorable response to
`controlled release form to achieve a favorable response to
`treatment.
`treatment.
`
`Arithmetic Mean (i SD) Plasma Concentration Profiles of 5-ASA
`Arithmetic Mean (1 SD) Plasma Concentration Profiles of 5-ASA
`After Administration of Single (Day 1, Period 1) and Multiple (Day
`After Administration of Single (Day 1, Period 1) and Multiple (Day
`14, Period 2) Doses of 2.4g/d QB
`14, Period 2) Doses of 2.4g/d QD
`
`3 E
`
`5000 ’
`6000 t
`
`5000 ’
`5000 *
`
`4000 ’
`4000 *
`
`3000 ’
`
`2000 ’
`
`
`
`W
`
`’
`i
`-—:
`3
`——
`1000’
`'
`[3
`‘T"""""‘7"""”:““
`0' K
`06121824
`
`,,
`,,
`7
`3 *fj\,i\1
`"""
`
`""""."""""'1""""" . """""‘I""""""."""""‘T"""""T
`
`36
`30
`42
`48
`54
`60
`66
`72
`30
`36
`42
`48
`54
`60
`66
`72
`Time post-dose (h)
`Time post—dose (h)
`
`E E
`
`
`
`
`
`Plasma concentration (ng/mL)
`
`E S
`
`§ g
`
`E
`L5
`0-
`
`I Day 1 (Period 1)
`' Day 1 (Period 1)
`
`E‘ Day 14 (Period 2)
`5' Day 14 (Period 2)
`
`— - - Lower limit of quantification (5.00 ng/mL)
`- - - Lower limit of quantification (5.00 ng/mL)
`
`MycoNovo, Inc.
`Foxhill Opportunity Fund, L.P.
`EX 1001
`
`
`
`Note: The lower half of the error—bar is not shown if it cuts the x—axis.
`Note: The lower half of the error-bar is not shown if it cuts the x-axis.
`
`

`
`Patent Application Publication
`Patent Application Publication
`
`Feb. 11, 2010 Sheet 1 0f 2
`Feb. 11, 2010 Sheet 1 of 2
`
`US 2010/0035850 A1
`US 2010/0035850 A1
`
`Figure 1: Arithmetic Mean (1 SD) Plasma Concentration Profiles of 5-ASA
`Figure 1: Arithmetic Mean (1 SD) Plasma Concentration Profiles of 5-ASA
`After Administration of Single (Day 1, Period 1) and Multiple (Day
`After Administration of Single (Day 1, Period 1) and Multiple (Day
`14, Period 2) Doses of 2.4g/d GD
`14, Period 2) Doses of 2.4g/d QD
`
`
`
`Plasmaconcentration(ng/mL)
`
`
`Plasma concentration (ng/mL)
`
`6000 ’
`6000 *
`
`5000
`5000
`
`4000 ’
`4000 *
`
`3000 ’
`3000 *
`
`2000 ’
`2000 *
`
`1000* a
`
`1000/ii
`,%£/
`
`x
`
`\
`
`\*\
`
`0
`
`6
`
`12
`
`_
`18
`
`1.
`”
`24
`24
`
`Ti
`42
`3‘6
`do
`48
`42
`36
`30
`48
`Time post-dose (h)
`Time post-dose (h)
`
`' Day 1 (Period 1)
`I Day 1 (Period 1)
`
`5' Day 14 (Period 2)
`E' Day 14 (Period 2)
`
`5‘4
`54
`
`60
`60
`
`66
`66
`
`72
`72
`
`— - — Lower limit of quantification (5.00 ng/mL)
`- - - Lower limit of quantification (5.00 ng/mL)
`
`Note: The lower half of the error-bar is not shown if it cuts the x-axis.
`Note: The lower half of the error-bar is not shown if it cuts the x-axis.
`
`

`
`Patent Application Publication
`Patent Application Publication
`
`Feb. 11, 2010 Sheet 2 0f 2
`Feb. 11, 2010 Sheet 2 of 2
`
`US 2010/0035850 A1
`US 2010/0035850 A1
`
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`
`US 2010/0035850 A1
`US 2010/0035850 A1
`
`Feb. 11, 2010
`Feb. 11, 2010
`
`METHOD OF TREATMENT FOR
`METHOD OF TREATMENT FOR
`INFLAMMATORY BOWEL DISEASE
`INFLAMMATORY BOWEL DISEASE
`
`[0001] This application claims priority to U.S. Provisional
`[0001] This application claims priority to US. Provisional
`Application No. 60/866,401, filed Nov. 17, 2006, the entire
`Application No. 60/866,401, ?led Nov. 17, 2006, the entire
`contents of which are incorporated herein by reference.
`contents of Which are incorporated herein by reference.
`
`BACKGROUND
`BACKGROUND
`
`[0002]
`Inflammatory bowel disease (IBD) is a term used in
`[0002] In?ammatory boWel disease (IBD) is a term used in
`the art to generically encompass diseases of the intestines
`the art to generically encompass diseases of the intestines
`such as ulcerative colitis (UC), irritable bowel syndrome,
`such as ulcerative colitis (U C), irritable boWel syndrome,
`irritable colon syndrome and Crohn’s disease (CD). For many
`irritable colon syndrome and Crohn’s disease (CD). For many
`ofthese diseases, in particular CD, the etiology ofthe disease
`of these diseases, in particular CD, the etiology of the disease
`(bacterial, viral, genetic, or autoimmune)
`is unknown.
`(bacterial, viral, genetic, or autoimmune) is unknown.
`Inflammatory bowel diseases such as CD or UC have been
`In?ammatory boWel diseases such as CD or UC have been
`treated in the past with salicylic acid derivatives (such as
`treated in the past With salicylic acid derivatives (such as
`5-aminosalicylic acid, also known as 5-ASA, mesalamine or
`5-aminosalicylic acid, also knoWn as 5-ASA, mesalamine or
`mesalazine; salts or esters of 5-ASA; and prodrugs of 5-ASA,
`mesalaZine; salts or esters of 5-ASA; and prodrugs of 5-ASA,
`such as sulfasalazine). 5-ASA is used as a first-line treatment
`such as sulfasalaZine). 5-ASA is used as a ?rst-line treatment
`for mild-to-moderate ulcerative colitis.
`for mild-to-moderate ulcerative colitis.
`[0003]
`It is known that doses of 5-ASA >2 g/day are no
`[0003] It is knoWn that doses of 5-ASA >2 g/day are no
`more effective than lower doses for maintaining remission in
`more effective than loWer doses for maintaining remission in
`patients with UC (Travis S, Nature Clinical Practice Gastro-
`patients With UC (Travis S, Nature Clinical Practice Gastro
`enterology & Hepatology (2005) 2, 564-565). Orally admin-
`enterology & Hepatology (2005) 2, 564-565). Orally admin
`istered 5-ASA acts locally from the luminal side of the
`istered 5-ASA acts locally from the luminal side of the
`inflamed bowel after absorption by the colonic and ileal
`in?amed boWel after absorption by the colonic and ileal
`mucosa, and is primarily acetylated to its major metabolite
`mucosa, and is primarily acetylated to its major metabolite
`N-acetyl-5-ASA (Ac-5-ASA) in the gut wall and the liver.
`N-acetyl-5-ASA (Ac-5-ASA) in the gut Wall and the liver.
`Current guidelines for the treatment of active mild-to-mod-
`Current guidelines for the treatment of active mild-to-mod
`erate UC suggest that oral 5-ASA treatment, as either mono-
`erate UC suggest that oral 5-ASA treatment, as either mono
`therapy or in combination with a topical formulation, should
`therapy or in combination With a topical formulation, should
`be prescribed for approximately 4 to 6 weeks for the induction
`be prescribed for approximately 4 to 6 Weeks for the induction
`of remission (Carter M J, et al. Gut 2004; 53:V1-16. and
`of remission (Carter M J, et al. Gut 2004; 53:V1-16. and
`Kombluth A, et al. Am J Gastroenterol 2004; 99:1371-85).
`Kombluth A, et al. Am J Gastroenterol 2004; 99:1371-85).
`[0004] However, ifpatients fail to achieve remission in this
`[0004] HoWever, if patients fail to achieve remission in this
`induction phase, there is no suggestion that continued 5-ASA
`induction phase, there is no suggestion that continued 5-ASA
`therapy under these conditions will result in the induction of
`therapy under these conditions Will result in the induction of
`remission. Therefore,
`the clinician must decide the next
`remission. Therefore, the clinician must decide the next
`appropriate step in the treatment paradigm, which is generally
`appropriate step in the treatment paradigm, Which is generally
`known as “step-up” therapy or “therapy escalation.” The next
`knoWn as “step-up” therapy or “therapy escalation.” The next
`“step” in this paradigm is generally corticosteroid therapy, a
`“step” in this paradigm is generally corticosteroid therapy, a
`therapy often not tolerated by patients due to its side effects.
`therapy often not tolerated by patients due to its side effects.
`[0005]
`Patients achieving remission from active, mild-to-
`[0005] Patients achieving remission from active, mild-to
`moderate UC are generally maintained in remission using
`moderate UC are generally maintained in remission using
`continued 5-ASA (aminosalicylate) therapy (Kornbluth A, et
`continued 5-ASA (aminosalicylate) therapy (Kornbluth A, et
`al. Am J Gastroenterol 2004; 99: 1371-85).
`al. Am J Gastroenterol 2004; 99: 1371-85).
`
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`
`[0006] The present invention involves a method of treat-
`[0006] The present invention involves a method of treat
`ment of a subject suffering from inflammatory bowel disease
`ment of a subject suffering from in?ammatory boWel disease
`such as ulcerative colitis (UC), comprising administering an
`such as ulcerative colitis (U C), comprising administering an
`initial daily dose of about 2.4-4.8 g of 5-ASA in controlled
`initial daily dose of about 2.4-4.8 g of 5-ASA in controlled
`release form and, when remission is not achieved after such
`release form and, When remission is not achieved after such
`treatment for about 4-8 weeks, changing the initial dose to a
`treatment for about 4-8 Weeks, changing the initial dose to a
`daily dosage equal to or greater than about 4 g of 5-ASA in
`daily dosage equal to or greater than about 4 g of 5-ASA in
`controlled release form for a period suflicient to achieve
`controlled release form for a period su?icient to achieve
`response to treatment.
`response to treatment.
`[0007] Once embodiment of the present invention provides
`[0007] Once embodiment of the present invention provides
`a treatment for the induction of remission in a patient suffer-
`a treatment for the induction of remission in a patient suffer
`ing from inflammatory bowel disease who has been unre-
`ing from in?ammatory boWel disease Who has been unre
`sponsive to 5-ASA administered at an oral daily dose of 2.4 g
`sponsive to 5-ASA administered at an oral daily dose of 2.4 g
`in controlled release form, administered as an oral 1.2 g
`in controlled release form, administered as an oral 1.2 g
`
`twice-daily dose, a 2.4 g once-daily dose or a 0.8 g thrice-
`tWice-daily dose, a 2.4 g once-daily dose or a 0.8 g thrice
`daily dose, wherein the daily dose is changed to a 4.8 g
`daily dose, Wherein the daily dose is changed to a 4.8 g
`once-daily dose for a period of up to 8 weeks until the patient
`once-daily dose for a period of up to 8 Weeks until the patient
`treated is in remission.
`treated is in remission.
`[0008] An alternate embodiment of the present invention
`[0008] An alternate embodiment of the present invention
`provides a method of treating a patient suffering from ulcer-
`provides a method of treating a patient suffering from ulcer
`ative colitis or other inflammatory bowel disease who has
`ative colitis or other in?ammatory boWel disease Who has
`been unresponsive to 5-ASA administered at an oral once-
`been unresponsive to 5-ASA administered at an oral once
`daily dose of 4.8 g, comprising administering to the patient a
`daily dose of 4.8 g, comprising administering to the patient a
`daily dose of 4.8 g of 5-ASA in controlled release form for a
`daily dose of 4.8 g of 5-ASA in controlled release form for a
`period of up to 8 weeks, until the patient treated is in remis-
`period of up to 8 Weeks, until the patient treated is in remis
`sron.
`sron.
`[0009]
`Formulations useful in the method of treatment of
`[0009] Formulations useful in the method of treatment of
`the present invention exhibit a single dose in vivo plasma
`the present invention exhibit a single dose in vivo plasma
`concentration profile substantially the same as that shown in
`concentration pro?le substantially the same as that shoWn in
`FIG. 1 and deliver the 5-ASA in a controlled-release manner.
`FIG. 1 and deliver the 5-ASA in a controlled-release manner.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0010]
`FIG. 1 depicts the arithmetic mean (:SD) plasma
`[0010] FIG. 1 depicts the arithmetic mean (:SD) plasma
`concentration profiles of 5-ASA after administration of single
`concentration pro?les of 5-ASA after administration of single
`(day 1, period 1) and multiple (day 14, period 2) doses of2.4
`(day 1, period 1) and multiple (day 14, period 2) doses of2.4
`g/d QD of MMX® mesalamine in normal health subjects.
`g/d QD of MMX® mesalamine in normal health subjects.
`Solid, filled-in squares are the data from day 1 (period 1);
`Solid, ?lled-in squares are the data from day 1 (period 1);
`open, unfilled squares are the data from day 14 (period 2). The
`open, un?lled squares are the data from day 14 (period 2). The
`dotted line represents the lower limit of quantification (5.00
`dotted line represents the loWer limit of quanti?cation (5.00
`ng/mL). The X-axis is time post-dose in hours and theY axis
`ng/mL). The X-axis is time post-dose in hours and theY axis
`is plasma concentration in ng/mL.
`is plasma concentration in ng/mL.
`[0011]
`FIG. 2 illustrates the plasma concentrations for con-
`[0011] FIG. 2 illustrates the plasma concentrations for con
`trolled release formulations of 5-ASA. Open, unfilled circles
`trolled release formulations of 5-ASA. Open, un?lled circles
`represent Asacol® (Norwich Eaton and Procter & Gamble),
`represent Asacol® (N orWich Eaton and Procter & Gamble),
`800 mg 5-ASA; open, unfilled squares represent Asacol®
`800 mg 5-ASA; open, un?lled squares represent Asacol®
`(Norwich Eaton and Procter & Gamble), 800 mg 5-ASA;
`(NorWich Eaton and Procter & Gamble), 800 mg 5-ASA;
`open, unfilled rectangles represent Colazol, balsalazide 2250
`open, un?lled rectangles represent ColaZol, balsalaZide 2250
`mg (Salix) (800 mg 5-ASA); open, unfilled triangles repre-
`mg (Salix) (800 mg 5-ASA); open, un?lled triangles repre
`sent Pentasa®, 1000 mg (Shire Pharmaceuticals) 5-ASA;
`sent Pentasa®, 1000 mg (Shire Pharmaceuticals) 5-ASA;
`open, unfilled, inverted triangles represent Salazopyrin-EN,
`open, un?lled, inverted triangles represent SalaZopyrin-EN,
`sulphasalazine 2000 mg (Watson Laboratories) (800 mg
`sulphasalaZine 2000 mg (Watson Laboratories) (800 mg
`5-ASA); solid, filled circles represent MMX® 5-ASA (Li-
`5-ASA); solid, ?lled circles represent MMX® 5-ASA (Li
`alda®, 2400 mg 5-ASA) (Cosmo S.p.A. of Milan); and solid,
`alda®, 2400 mg 5-ASA) (Cosmo S.p.A. of Milan); and solid,
`filled squares represent MMX® (Lialda®, 4800 mg 5-ASA)
`?lled squares represent MMX® (Lialda®, 4800 mg 5-ASA)
`(Cosmo S.p.A. of Milan). The X-axis is time after dosing in
`(Cosmo S.p.A. of Milan). The X-axis is time after dosing in
`hours and the Y axis is plasma concentration of 5-ASA in
`hours and the Y axis is plasma concentration of 5-ASA in
`ng/mL. All concentration levels shown are after only a single
`ng/mL. All concentration levels shoWn are after only a single
`dose ofmedication was administered (i.e., after day 1 admin-
`dose of medication Was administered (i.e., after day 1 admin
`istration).
`istration).
`DETAILED DESCRIPTION OF THE INVENTION
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0012] Definitions
`[0012] De?nitions
`[0013] As used herein, the following terms have the mean-
`[0013] As used herein, the folloWing terms have the mean
`ings given beloW:
`ings given below:
`[0014]
`Subjects or patients refer to mammals suffering
`[0014] Subjects or patients refer to mammals suffering
`from inflammatory bowel disease, including but not limited
`from in?ammatory boWel disease, including but not limited
`to humans.
`to humans.
`[0015]
`Inflammatory bowel disease refers to diseases ofthe
`[0015] In?ammatory boWel disease refers to diseases of the
`intestines including ulcerative colitis (UC) (including mild-
`intestines including ulcerative colitis (UC) (including mild
`to-moderate ulcerative colitis which has a score of4-10 on the
`to-moderate ulcerative colitis Which has a score of 4-10 on the
`UC-disease activity index (UC-DAI), with a sigmoidoscopy
`UC-disease activity index (UC-DAI), With a sigmoidoscopy
`score of :4 and a Physician’s Global Assessment (PGA)
`score of 24 and a Physician’s Global Assessment (PGA)
`score of :2), irritable colon syndrome and Crohn’s disease.
`score of 22), irritable colon syndrome and Crohn’s disease.
`[0016] Controlled release forms of 5-ASA include any
`[0016] Controlled release forms of 5-ASA include any
`orally administrable dosage form which exhibits a single dose
`orally administrable dosage form Which exhibits a single dose
`in vivo plasma concentration profile substantially the same as
`in vivo plasma concentration pro?le substantially the same as
`that shown in FIG. 1 and delivers the 5-ASA in a controlled-
`that shoWn in FIG. 1 and delivers the 5-ASA in a controlled
`
`

`
`US 2010/0035850 A1
`US 2010/0035850 A1
`
`Feb. 11, 2010
`Feb. 11, 2010
`
`release manner. Various controlled release dosage forms of
`release manner. Various controlled release dosage forms of
`5-ASA are known in the art, including Asacol® (Norwich
`5-ASA are known in the art, including Asacol® (Norwich
`Eaton and Procter & Gamble), Colazol (Salix), Balsalazide
`Eaton and Procter & Gamble), ColaZol (Salix), BalsalaZide
`(Salix), Pentasa® (Shire Pharmaceuticals), Salazopysin-EN
`(Salix), Pentasa® (Shire Pharmaceuticals), SalaZopysin-EN
`sulphasalazine (Watson Laboratories) and MMX® Lialda®
`sulphasalaZine (Watson Laboratories) and MMX® Lialda®
`(Cosmo S.p.A. of Milan)
`(Cosmo S.p.A. of Milan)
`[0017] An
`exemplary
`controlled
`release
`form of
`[0017] An exemplary controlled release form of
`mesalamine is MMX Multi Matrix System® (MMX®)
`mesalamine is MMX Multi Matrix System® (MMX®)
`mesalamine (LialdaTM, also known as MezavantTM XL in the
`mesalamine (LialdaTM, also knoWn as MeZavantTM XL in the
`UK and Ireland, and MezavantTM elsewhere), described in
`UK and Ireland, and MeZavantTM elseWhere), described in
`U.S. Pat. No. 6,773,720 to Villa et al., which is incorporated
`US. Pat. No. 6,773,720 to Villa et al., Which is incorporated
`herein by reference. While no specific dosage is required for
`herein by reference. While no speci?c dosage is required for
`MMX® mesalamine, an exemplary MMX® mesalamine is a
`MMX® mesalamine, an exemplary MMX® mesalamine is a
`controlled-release oral pharmaceutical composition contain-
`controlled-release oral pharmaceutical composition contain
`ing as an active ingredient 1.2 grams of 5-ASA, comprising a
`ing as an active ingredient 1.2 grams of 5-ASA, comprising a
`multimatrix core consisting of a lipophilic matrix and a
`multimatrix core consisting of a lipophilic matrix and a
`hydrophilic matrix wherein the active ingredient is dispersed.
`hydrophilic matrix Wherein the active ingredient is dispersed.
`In the exemplary formulation, the active ingredient is present
`In the exemplary formulation, the active ingredient is present
`in an amount over 80%, generally 80-95%, by weight of the
`in an amount over 80%, generally 80-95%, by Weight of the
`total composition.
`total composition.
`[0018] The exemplary controlled-release formulation com-
`[0018] The exemplary controlled-release formulation com
`prises a) an inner lipophilic matrix of unsaturated and/or
`prises a) an inner lipophilic matrix of unsaturated and/or
`hydrogenated fatty acid, salts, esters or amides thereof, fatty
`hydrogenated fatty acid, salts, esters or amides thereof, fatty
`acid mono-, di- or triglycerides, waxes, ceramides, and cho-
`acid mono-, di- or triglycerides, Waxes, ceramides, and cho
`lesterol derivatives with melting points below 90° C., wherein
`lesterol derivatives With melting points beloW 90° C., Wherein
`the active ingredient is dispersed in both the lipophilic matrix
`the active ingredient is dispersed in both the lipophilic matrix
`and the hydrophilic matrix; b) an outer hydrophilic matrix
`and the hydrophilic matrix; b) an outer hydrophilic matrix
`wherein the lipophilic matrix is dispersed, and wherein the
`Wherein the lipophilic matrix is dispersed, and Wherein the
`outer hydrophilic matrix is a polymer of acrylic or meth-
`outer hydrophilic matrix is a polymer of acrylic or meth
`acrylic acid, an alkylvinyl polymer, a hydroxyalkyl cellulose,
`acrylic acid, an alkylvinyl polymer, a hydroxyalkyl cellulose,
`carboxyalkyl cellulose, polysaccharide, dextrin, pectin,
`carboxyalkyl cellulose, polysaccharide, dextrin, pectin,
`starch or starch derivative, alginic acid, or a natural or syn-
`starch or starch derivative, alginic acid, or a natural or syn
`thetic gum; and c) optionally other excipients.
`thetic gum; and c) optionally other excipients.
`[0019] Approved treatments of inflammatory bowel dis-
`[0019] Approved treatments of in?ammatory boWel dis
`ease with 5-ASA utilize daily doses of 2.4 or 4.8 g of the
`ease With 5-ASA utiliZe daily doses of 2.4 or 4.8 g of the
`controlled release dosage forms. As indicated above, when
`controlled release dosage forms. As indicated above, When
`such treatments do not achieve remission, in accordance with
`such treatments do not achieve remission, in accordance With
`the present invention a controlled release form of 5-ASA is
`the present invention a controlled release form of 5-ASA is
`administered in a daily dosage equal to or greater than about
`administered in a daily dosage equal to or greater than about
`4 g, preferably about 4-5 g, generally for about 4 to 8 weeks,
`4 g, preferably about 4-5 g, generally for about 4 to 8 Weeks,
`to achieve remission.
`In accordance with the preferred
`to achieve remission. In accordance With the preferred
`embodiments hereof,
`the treatment of the invention is
`embodiments hereof, the treatment of the invention is
`employed with the currently approved controlled release regi-
`employed With the currently approved controlled release regi
`mens for the treatment of inflammatory bowel disease,
`mens for the treatment of in?ammatory boWel disease,
`namely, a 2.4 g daily dose (administered in equal amounts
`namely, a 2.4 g daily dose (administered in equal amounts
`once, twice or three times a day) or a 4.8 g daily dose (admin-
`once, tWice or three times a day) or a 4.8 g daily dose (admin
`istered once a day) when remission is not achieved after about
`istered once a day) When remission is not achieved after about
`4-8 weeks of such treatments. Utilizing the approved con-
`4-8 Weeks of such treatments. Utilizing the approved con
`trolled release dosage forms, the treatment of the present
`trolled release dosage forms, the treatment of the present
`invention is usually carried out with a 4.8 g daily dose, pref-
`invention is usually carried out With a 4.8 g daily dose, pref
`erably with the once-daily administration of the requisite
`erably With the once-daily administration of the requisite
`controlled release dosage form, to achieve remission.
`controlled release dosage form, to achieve remission.
`[0020] As further used herein, remission refers to applica-
`[0020] As further used herein, remission refers to applica
`tion of the customary markers utilized in clinical practice to
`tion of the customary markers utiliZed in clinical practice to
`assess IBD. For example, a patient is considered to be in
`assess IBD. For example, a patient is considered to be in
`remission for UC if a UC-DAI score of §1 is obtained, with
`remission for UC if a UC-DAI score of E1 is obtained, With
`rectal bleeding and stool frequency scores of 0, and at least a
`rectal bleeding and stool frequency scores of 0, and at least a
`1-point reduction in sigmoidoscopy score from baseline.
`1-point reduction in sigmoidoscopy score from baseline.
`Remission also involves a Physician’s Global Assessment
`Remission also involves a Physician’s Global Assessment
`(PGA) of §1 and no mucosal friability. In some cases, a
`(PGA) of E1 and no mucosal friability. In some cases, a
`clinical response in which one or more ofthe above criteria of
`clinical response in Which one or more of the above criteria of
`remission are met is considered a significant patient response.
`remission are met is considered a signi?cant patient response.
`Such responses, although not indicative oftotal remission, are
`Such responses, although not indicative of total remission, are
`indicators of a favorable response to treatment.
`indicators of a favorable response to treatment.
`
`[0021]
`It will be understood that the treatment of the
`[0021] It Will be understood that the treatment of the
`present invention may not achieve total remission in any or all
`present invention may not achieve total remission in any or all
`patients treated in accordance therewith, the degree of remis-
`patients treated in accordance thereWith, the degree of remis
`sion depending on the nature and degree of the disease in any
`sion depending on the nature and degree of the disease in any
`particular patient.
`particular patient.
`[0022]
`In an embodiment ofthe present invention, the treat-
`[0022] In an embodiment of the present invention, the treat
`ment of the invention for the induction of remission in
`ment of the invention for the induction of remission in
`patients suffering from UC which have been unresponsive to
`patients suffering from UC Which have been unresponsive to
`5-ASA results in, 5-ASA Cm“ value greater than about 2800
`5-ASA results in, 5-ASA Cmax value greater than about 2800
`r1g/ML and an area under the curve (AUC) greater than about
`ng/ ML and an area under the curve (AUC) greater than about
`21,000 ng.h/mL for a period between about 6 to about 18
`21,000 ng.h/mL for a period betWeen about 6 to about 18
`weeks or until the treated patient obtains a UC-DAI score § 1 .
`Weeks or until the treated patient obtains a UC-DAI score 21 .
`[0023]
`Formulations useful in the treatment of the present
`[0023] Formulations useful in the treatment of the present
`invention exhibit a single dose in vivo plasma concentration
`invention exhibit a single dose in vivo plasma concentration
`profile substantially the same as that shown in FIG. 1. The
`pro?le substantially the same as that shoWn in FIG. 1. The
`latter shows the Arithmetic Mean (:SD) (over about 100
`latter shoWs the Arithmetic Mean (:SD) (over about 100
`patients) plasma concentration profile achieved for 5-ASA in
`patients) plasma concentration pro?le achieved for 5-ASA in
`MMX® mesalamine in normal, healthy subjects. The formu-
`MMX® mesalamine in normal, healthy subjects. The formu
`lations of the instant invention should achieve substantially
`lations of the instant invention should achieve substantially
`the same mean plasma concentration curves as those shown in
`the same mean plasma concentration curves as those shoWn in
`FIG. 1 and Table 2 below. By substantially the same “profile”
`FIG. 1 and Table 2 beloW. By substantially the same “pro?le”
`herein is meant that two curves have substantially the same
`herein is meant that tWo curves have substantially the same
`AUC (area under the curve) and CW”, e.g., these parameters
`AUC (area under the curve) and Cm“, e. g., these parameters
`for each curve are 120% of each other, or even closer, e.g
`for each curve are 120% of each other, or even closer, eg
`110%, 15%, 12%, etc., which parameters are conventionally
`110%, 15%, 12%, etc., Which parameters are conventionally
`determined. See, e.g., Fundamentals of Clinical Pharmacoki-
`determined. See, e.g., Fundamentals of Clinical Pharmacoki
`netics. J. G. Wagner, Drug Intelligence Publications, Inc.,
`netics. J. G. Wagner, Drug Intelligence Publications, Inc.,
`Hamilton, Ill., 1975; Guidance for Industry, Bioavailability
`Hamilton, Ill., 1975; Guidance for Industry, Bioavailability
`and Bioequivalence Studies for Orally Administered Drug
`and Bioequivalence Studies for Orally Administered Drug
`Products-General Considerations, FDA, CDER. October
`Products-General Considerations, FDA, CDER. October
`2000.
`2000.
`
`EXAMPLES
`EXAMPLES
`
`Example 1
`Example 1
`[0024] The induction ofremission ofmild-to-moderate UC
`[0024] The induction of remission of mild-to-moderate UC
`during therapy with MMX® mesalamine 2.4 g/day once or
`during therapy With MMX® mesalamine 2.4 g/day once or
`twice daily (QD or BID) (4.8 g/day QD) was evaluated in two
`tWice daily (QD or BID) (4.8 g/day QD) Was evaluated in tWo
`phase III, placebo-controlled, randomized studies (SPD476-
`phase III, placebo-controlled, randomiZed studies (SPD476
`301 and -302). Study 302 also included an active internal
`301 and -302). Study 302 also included an active internal
`reference arm (Asacol® 2.4 g/day given three times daily).
`reference arm (Asacol® 2.4 g/day given three times daily).
`[0025] Remission was defined in the studies using stringent
`[0025] Remission Was de?ned in the studies using stringent
`criteria as a modified UC-DAI score of §1 calculated as
`criteria as a modi?ed UC-DAI score of E1 calculated as
`scores of 0 for rectal bleeding and stool frequency, a com-
`scores of 0 for rectal bleeding and stool frequency, a com
`bined Physician’s Global Assessment and sigmoidoscopy
`bined Physician’s Global Assessment and sigmoidoscopy
`score of § 1, no mucosal friability and at least a 1-point
`score of 21, no mucosal friability and at least a 1-point
`reduction in sigmoidoscopy score from baseline. Patients
`reduction in sigmoidoscopy score from baseline. Patients
`who did not achieve remission in studies 301 or 302 could opt
`Who did not achieve remission in studies 301 or 302 could opt
`to receive an additional 8 weeks’ therapy (at a dose of 4.8
`to receive an additional 8 Weeks’ therapy (at a dose of 4.8
`g/day given as 2.4 g BID) as part of an open-label study
`g/day given as 2.4 g BID) as part of an open-label study
`(SPD476-303). This part of the study was labeled the Acute,
`(SPD476-303). This part of the study Was labeled the Acute,
`or Extension, Phase.
`or Extension, Phase.
`[0026] The UC-DAI consisted of rectal bleeding, stool fre-
`[0026] The UC-DAI consisted of rectal bleeding, stool fre
`quency and sigmoidoscopy scores and PGA. Each of these
`quency and sigmoidoscopy scores and PGA. Each of these
`parameters was assessed on a scale of 0 to 3, with 3 being the
`parameters Was assessed on a scale of 0 to 3, With 3 being the
`most severe score. The sum of scores for all four parameters
`most severe score. The sum of scores for all four parameters
`determined the UC-DAI score. Assessment of sigmoido-
`determined the UC-DAI score. Assessment of sigmoido
`scopic appea