April NM
`
`(cid:9) (cid:9)
`
`4TTENUATION OF RESPONSE TO MULTIPLE RETRF.ATMENT
`kpuiXIIIIAR INFUSIONS FOR ACTIVE CROHN'S IHSFASE
`160; puTENTIAL FACTORS THAT MINIMIZE DECREASED
`RESPONSE,
`ILam, Eric A. Vasil iauskas, Maria T. Abreu, Philip V. Hassand,
`Lei
`geiceich, Joanne Gatennie, Laura Record, Thomas F. Schaible,
`
`F. Taiwan. Cedars-Sinai Mcd Ctr. Los Angeles, CA; Centocor,
`Stephan
`efee ern, PA.
`Initial Inniximale(5-20mg/kg) treatment(tx) for active CD is associated
`with a 65% response and 33% remission rate at 4 wks. However, the
`efficacy of Infliximab rctreatment(retx) for CD flare is unclear. AIM: to
`.4o1y me elliacy and safety of open labeled retx hdlixintab(5mg/kg) for
`recurrent CD. Methods: Grourngiell enrolled in Centocor C01 (cid:9)
`16 &
`em64e24 trials between 8/1/95 - 11130/98. Pts received Infliximab(5-
`-elmgete) for CDAI >220, then 0-4 maintenance infusions(inf) Q8wks X
`4. After 2A yrs(mean1.1.3 retx infsii5mg/kgi for CDAI (cid:9)
`21.16 were given,
`ekes were kept stable. Gp 2:enrollersent between 10/20198- 11/1/99. After
`Leda infi5tagiarge 1-2 vets infs(5mgfkg)fur CDAI > 15(1 were given.
`Change in reeds were allowed. CDAI was dune at wk 0. and 4 after each
`eiresiort. Response = j CDA1a70, or achievement of CDAI s 150. Re.
`mission = CDAIs150. Results: A significant decreasing trend in ACDAI
`sficr retx lots occurred in Gpl(p=.0116),laut not Gp2tp=.2.879). In Gp 1.
`"1:..resp and remission was also lower with retx. In Gp2. median 3,CDAI
`in % rasp and remission was minimal. Gp2
`after rets#1 decreased. but (cid:9)
`median wk0 CDAls were progressively lower with retie One delayed
`hypersensitivity rm. occurred in each Gp I & Gp 2. Gp I; mean #day5 last
`inf#1 e. 863. Op 2; Mail *days between inf
`maintenance inf (cid:9)
`1eirem#1 = 82,and retx#1--k- *2 =107. 82% in Op 2 were txd with
`6MPAZA or MTX vs 20% in Op I. Conclusion: Concurrent use of
`ironemorrieduLatory drugs with Inflixisnati therapy, and early retreatment
`fee CD flares may limit potential attenuation of response to multiple
`infusions.
`
`Oros* 1
`
`Group 2
`
`irltisiar. a
`N
`Idiumirb rnsIll
`Median Cat) s
`(cid:9) 0
`Median .1 .\ CDAI ..
`Fess I%/ •
`Renisport 4%).
`
`1
`tO
`5,10,20
`291
`160
`7(70)
`5(501
`
`Rat( 1 Reot 2 Rale 3
`10
`5
`9
`5
`5
`5
`333
`327
`264
`68
`53
`7
`7470/ NA
`2040
`04I
`21201
`2124
`
`1
`11
`5
`286
`178
`9021
`6(731
`
`RI* 1 Rani 2
`10
`5
`5
`5
`273
`230
`111
`182
`4450)
`4931
`411301
`60901
`
`- n.
`
`3598
`A RANDOMIZED CONTROLLED TRIAL OF CDP571, A HUMAN-
`IZED ANTIROI)'i TO TNFA, IN MODERATELY TO SEVERELY
`ACTIVE CROHN'S DISEASE.
`William 1, Sandlwirn, Stephan R. Targan, Stephen Ia. Hanauer, Daniel H.
`Present. Lloyd R. Sutherland, Michael A. Kamm, Doug C. Wolf, J. P.
`Baker, Christopher J. Hawkey. Patricia K. Heath, Brian G. Feagan, Mayo
`Clio. Rochester. MN; Cedars-Sinai Med Ctr, Los Angeles, CA; Univ of
`Chicago. Chicago, IL; Mount Sinai Sch of Medicine, New York, NY; Univ
`of Calgary. Calgary. AB, Canada; St Mark's Hosp. London, United King-
`dam: Atlanta Gastroenterology Assoc, Atlanta, GA; Univ of Toronto,
`Toronto. ON, Canada; Univ Hosp. Nottingham. United Kingdom; Celltech/
`Chirescientx, Slough, United Kingdom: Univ of Western Ontario, London,
`ON, Canada_
`BACKGROUND: Tumor necrosis factor (TNF) re plays a pivotal role in
`the inflammation of Cmhn's disease (CD). AIMS: To determine the eine
`caey and safety of the humanized anti-TNF antibody. CDP571, for induc-
`tion and maintenance of clinical improvement in patients with moderate to
`.everely active Crohr's disease. METHODS: 169 adult patients with
`nesecrate to severely active CD (CDA1 score 220-4501 were enrolled into
`J 24 week study and randomized to one of six treatment arms: I) CDP571
`:0 metikg at week 0 followed by 10 mg/kg at weeks 8 and 16; 2) CDP571
`10 nig/kg at weeks 0. 8, and 16; 3) placebo at weeks 0, 8. and 16; 4)
`CDP571 20 mg/kg at week 0 followed by 10 mg/kg at week 12; 5) CDP571
`10 mg/kg at weeks 0 and 12; and 6) placebo at weeks 0 and 12. Concern-
`ment medications were held constant at the pre-study dose, The Croho's
`
`AGA AASS
`
`disease activity index (CDAI) score was determined serially throughout the
`study. Clinical improvement was defined as a decrease in the CDAI score
`of > 70 points from the week 0 score. RESULTS: Clinical improvement
`at week 2 occurred in 15/56 (27%) of the placebo group, 29154 (54%) of
`the 10 mg/kg group (p=0_005); and 21/57 (37%) of the 20 mg/kg group
`(p.‘0.256). The survival curve of time to withdrawal during the 24 weeks
`study was significant for CDP57I compared to placebo for the 12 week
`dosing group (p=0.012) but not the 8 week dosing group (p=0.2291. The
`median change in CDAI for the I Orngfkg 12 weekly dosing group remained
`70 points below baseline throughout the 24 weeks of the study. Two of 13
`(15%) of placebo patients with draining fistiala.s at entry had closure of
`>1= 505E. of fistulas during the study compared with 12/24 (50%) in the
`CDP57I groups ip,-0.074). The frequency of adverse events AEs) were
`similar in the CDP571 and placebo groups: AEs at the time of infusion
`were 12% vs 7% (placeboXp=0.424); infections 14% vs 10% p=0.631);
`anti-CDP571 antibodies 9% vs (1% (p=0,016); and natimucleur antibodies
`plus anti- asDNA 7% vs 0% (p=0.052). There were no cases of lymphoma,
`drug induced lupus, or delayed hypersensitivity reactions in the study.
`CONCLUSIONS: CDP57I is effective in inducing clinical response at two
`weeks in patients with moderately to severely active Crohn s disease. The
`optimal dose Ls 10 mg/kg. Benefit was seen with repeat dosing and the
`optimal dosing frequency is every 12 weeks. CDP57I also closes draining
`tistid.es. CDP57I is safe and well tolerated, Support: Celhech/Chimerience.
`
`3599
`A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED,
`MULTI-CENTER TRIAL OF THE ENGINEERED HUMAN ANTI-
`BODY TO TNF (CDP5711 FOR STEROID SPARING AND MAIN-
`TENANCE OF REMISSION IN PATIENTS WITH STEROID-DE-
`PENDENT CROHN'S DISEASE.
`Brian G. Ragan, William J. Sandborn, J. P. Baker. F. Cominelli, Lloyd R.
`Sutherland, C. D. Elson. Bruce Salzberg., A. Archambauh. Charles N.
`Bernstein. G. R. Lichtenstein, Patricia K. Heath, Stephen B. Hanauer.
`London Clin Trials Research Group, London. ON, Canada; Mayo Clio,
`Rochester, MN; Univ of Toronto, Toronto, ON, Canada; Univ of Virginia.
`Charlottesville, VA; Univ of Calgary. Calgary. AB, Canada; Urns. of
`Alabama at Birmingham, Birmingham, AL; Atlanta Gastroenterology' As-
`soc, Atlanta, GA; Univ of Montreal, Montreal. PQ. Canada: Univ of
`Manitoba, Winnipeg. M13, Canada; Univ of Pennsylvania, Philadelphia,
`PA; Celltech Therapeutics Inc, Slough, United Kingdom; Univ of Chicago
`Hospitals, Chicago. IL.
`BACKGROUND: Tumour necrosis freetor(TNFOr plays a pivotal role in
`the inflammation of Crulan's disease (CD). We determined the efficacy and
`safety of humanized anti-TNF antibody, CDP571, for steroid sparing and
`maintenance of remission in patients with steroid-dependent CD, METH-
`ODS: 71 patients with steruid-dependent CD (CDAI < 150, AND a
`prednimme dose of 15-40 mg/day or a budesrmide dose of 9mghlay for >
`8 weeks, AND a failed attempt to taper prednisone or budesanide within 8
`weeks) were enrolled into a 16 week study and randomized to one of two
`treatments: 1) CDP571 20 mg/kg at week 0 followed by 10 mg/kg at week
`8; 2) placebo at weeks 0 and 8. Predoisone was decreased from the week
`0 dose by 5 mg/week to a dose of 10 mg/day, and then by 2.5 mg/week
`until discontinuation. Budesonide was decreased from 9 mg/day to 6
`meduy for 3 weeks, 3 mg/day for 3 weeks, and then discontinued.
`5-Aminosalicylatee, patine antimemholites and methotremne were held
`constant at the pre-study dose. The primary outcome was defined as total
`steroid withdrawal without a flare of CD (increase in CDAI to > 220
`points). RESULTS: 39 patients received CDP571 and 32 received placebo:
`the demographic characteristics of the patients were not different in the two
`groups. At week 40, 17/39 (43.6%) of patients who received CDP571
`remained free of a disease flare as compered with only 7/32 (21.9 %) of
`thuse who received placebo (P = 0.049). CDP57I therapy was well
`tolerated. No severe infusion reactions were identified, Serious adverse
`events occurred in 12.5% of patients receiving placebo and 17.9% of those
`assigned to active treatment; the majority of these were disease related and
`none were attributed tee CDP571 therapy, Only one patient (2.6%) devel-
`oped detectable antibody to CDP57I. 6.7% of patients developed anti-
`dont-Fie-stranded DNA antibodies. No CILSC5 of lupus or lymphoma oc-
`curred. CONCLUSIONS: CDP57 I is an effective therapy which facilitates
`withdrawal of coniecisteroids in adults with chronic steroid dependent CD.
`Therapy with CDP571 is associated with a low incidence of adverse events.
`A low race of auto-antibody formation was mime and antibodies to
`CDP571 occurred infrequently.
`
`Ex. 1099 - Page 1
`
`
`
`(cid:9) (cid:9)
`
`4TTENUATION OF RESPONSE TO MULTIPLE RETRF.ATMENT
`kpuiXIIIIAR INFUSIONS FOR ACTIVE CROHN'S IHSFASE
`160; puTENTIAL FACTORS THAT MINIMIZE DECREASED
`RESPONSE,
`ILam, Eric A. Vasil iauskas, Maria T. Abreu, Philip V. Hassand,
`Lei
`geiceich, Joanne Gatennie, Laura Record, Thomas F. Schaible,
`
`F. Taiwan. Cedars-Sinai Mcd Ctr. Los Angeles, CA; Centocor,
`Stephan
`efee ern, PA.
`Initial Inniximale(5-20mg/kg) treatment(tx) for active CD is associated
`with a 65% response and 33% remission rate at 4 wks. However, the
`efficacy of Infliximab rctreatment(retx) for CD flare is unclear. AIM: to
`.4o1y me elliacy and safety of open labeled retx hdlixintab(5mg/kg) for
`recurrent CD. Methods: Grourngiell enrolled in Centocor C01 (cid:9)
`16 &
`em64e24 trials between 8/1/95 - 11130/98. Pts received Infliximab(5-
`-elmgete) for CDAI >220, then 0-4 maintenance infusions(inf) Q8wks X
`4. After 2A yrs(mean1.1.3 retx infsii5mg/kgi for CDAI (cid:9)
`21.16 were given,
`ekes were kept stable. Gp 2:enrollersent between 10/20198- 11/1/99. After
`Leda infi5tagiarge 1-2 vets infs(5mgfkg)fur CDAI > 15(1 were given.
`Change in reeds were allowed. CDAI was dune at wk 0. and 4 after each
`eiresiort. Response = j CDA1a70, or achievement of CDAI s 150. Re.
`mission = CDAIs150. Results: A significant decreasing trend in ACDAI
`sficr retx lots occurred in Gpl(p=.0116),laut not Gp2tp=.2.879). In Gp 1.
`"1:..resp and remission was also lower with retx. In Gp2. median 3,CDAI
`in % rasp and remission was minimal. Gp2
`after rets#1 decreased. but (cid:9)
`median wk0 CDAls were progressively lower with retie One delayed
`hypersensitivity rm. occurred in each Gp I & Gp 2. Gp I; mean #day5 last
`inf#1 e. 863. Op 2; Mail *days between inf
`maintenance inf (cid:9)
`1eirem#1 = 82,and retx#1--k- *2 =107. 82% in Op 2 were txd with
`6MPAZA or MTX vs 20% in Op I. Conclusion: Concurrent use of
`ironemorrieduLatory drugs with Inflixisnati therapy, and early retreatment
`fee CD flares may limit potential attenuation of response to multiple
`infusions.
`
`Oros* 1
`
`Group 2
`
`irltisiar. a
`N
`Idiumirb rnsIll
`Median Cat) s
`(cid:9) 0
`Median .1 .\ CDAI ..
`Fess I%/ •
`Renisport 4%).
`
`1
`tO
`5,10,20
`291
`160
`7(70)
`5(501
`
`Rat( 1 Reot 2 Rale 3
`10
`5
`9
`5
`5
`5
`333
`327
`264
`68
`53
`7
`7470/ NA
`2040
`04I
`21201
`2124
`
`1
`11
`5
`286
`178
`9021
`6(731
`
`RI* 1 Rani 2
`10
`5
`5
`5
`273
`230
`111
`182
`4450)
`4931
`411301
`60901
`
`- n.
`
`3598
`A RANDOMIZED CONTROLLED TRIAL OF CDP571, A HUMAN-
`IZED ANTIROI)'i TO TNFA, IN MODERATELY TO SEVERELY
`ACTIVE CROHN'S DISEASE.
`William 1, Sandlwirn, Stephan R. Targan, Stephen Ia. Hanauer, Daniel H.
`Present. Lloyd R. Sutherland, Michael A. Kamm, Doug C. Wolf, J. P.
`Baker, Christopher J. Hawkey. Patricia K. Heath, Brian G. Feagan, Mayo
`Clio. Rochester. MN; Cedars-Sinai Med Ctr, Los Angeles, CA; Univ of
`Chicago. Chicago, IL; Mount Sinai Sch of Medicine, New York, NY; Univ
`of Calgary. Calgary. AB, Canada; St Mark's Hosp. London, United King-
`dam: Atlanta Gastroenterology Assoc, Atlanta, GA; Univ of Toronto,
`Toronto. ON, Canada; Univ Hosp. Nottingham. United Kingdom; Celltech/
`Chirescientx, Slough, United Kingdom: Univ of Western Ontario, London,
`ON, Canada_
`BACKGROUND: Tumor necrosis factor (TNF) re plays a pivotal role in
`the inflammation of Cmhn's disease (CD). AIMS: To determine the eine
`caey and safety of the humanized anti-TNF antibody. CDP571, for induc-
`tion and maintenance of clinical improvement in patients with moderate to
`.everely active Crohr's disease. METHODS: 169 adult patients with
`nesecrate to severely active CD (CDA1 score 220-4501 were enrolled into
`J 24 week study and randomized to one of six treatment arms: I) CDP571
`:0 metikg at week 0 followed by 10 mg/kg at weeks 8 and 16; 2) CDP571
`10 nig/kg at weeks 0. 8, and 16; 3) placebo at weeks 0, 8. and 16; 4)
`CDP571 20 mg/kg at week 0 followed by 10 mg/kg at week 12; 5) CDP571
`10 mg/kg at weeks 0 and 12; and 6) placebo at weeks 0 and 12. Concern-
`ment medications were held constant at the pre-study dose, The Croho's
`
`AGA AASS
`
`disease activity index (CDAI) score was determined serially throughout the
`study. Clinical improvement was defined as a decrease in the CDAI score
`of > 70 points from the week 0 score. RESULTS: Clinical improvement
`at week 2 occurred in 15/56 (27%) of the placebo group, 29154 (54%) of
`the 10 mg/kg group (p=0_005); and 21/57 (37%) of the 20 mg/kg group
`(p.‘0.256). The survival curve of time to withdrawal during the 24 weeks
`study was significant for CDP57I compared to placebo for the 12 week
`dosing group (p=0.012) but not the 8 week dosing group (p=0.2291. The
`median change in CDAI for the I Orngfkg 12 weekly dosing group remained
`70 points below baseline throughout the 24 weeks of the study. Two of 13
`(15%) of placebo patients with draining fistiala.s at entry had closure of
`>1= 505E. of fistulas during the study compared with 12/24 (50%) in the
`CDP57I groups ip,-0.074). The frequency of adverse events AEs) were
`similar in the CDP571 and placebo groups: AEs at the time of infusion
`were 12% vs 7% (placeboXp=0.424); infections 14% vs 10% p=0.631);
`anti-CDP571 antibodies 9% vs (1% (p=0,016); and natimucleur antibodies
`plus anti- asDNA 7% vs 0% (p=0.052). There were no cases of lymphoma,
`drug induced lupus, or delayed hypersensitivity reactions in the study.
`CONCLUSIONS: CDP57I is effective in inducing clinical response at two
`weeks in patients with moderately to severely active Crohn s disease. The
`optimal dose Ls 10 mg/kg. Benefit was seen with repeat dosing and the
`optimal dosing frequency is every 12 weeks. CDP57I also closes draining
`tistid.es. CDP57I is safe and well tolerated, Support: Celhech/Chimerience.
`
`3599
`A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED,
`MULTI-CENTER TRIAL OF THE ENGINEERED HUMAN ANTI-
`BODY TO TNF (CDP5711 FOR STEROID SPARING AND MAIN-
`TENANCE OF REMISSION IN PATIENTS WITH STEROID-DE-
`PENDENT CROHN'S DISEASE.
`Brian G. Ragan, William J. Sandborn, J. P. Baker. F. Cominelli, Lloyd R.
`Sutherland, C. D. Elson. Bruce Salzberg., A. Archambauh. Charles N.
`Bernstein. G. R. Lichtenstein, Patricia K. Heath, Stephen B. Hanauer.
`London Clin Trials Research Group, London. ON, Canada; Mayo Clio,
`Rochester, MN; Univ of Toronto, Toronto, ON, Canada; Univ of Virginia.
`Charlottesville, VA; Univ of Calgary. Calgary. AB, Canada; Urns. of
`Alabama at Birmingham, Birmingham, AL; Atlanta Gastroenterology' As-
`soc, Atlanta, GA; Univ of Montreal, Montreal. PQ. Canada: Univ of
`Manitoba, Winnipeg. M13, Canada; Univ of Pennsylvania, Philadelphia,
`PA; Celltech Therapeutics Inc, Slough, United Kingdom; Univ of Chicago
`Hospitals, Chicago. IL.
`BACKGROUND: Tumour necrosis freetor(TNFOr plays a pivotal role in
`the inflammation of Crulan's disease (CD). We determined the efficacy and
`safety of humanized anti-TNF antibody, CDP571, for steroid sparing and
`maintenance of remission in patients with steroid-dependent CD, METH-
`ODS: 71 patients with steruid-dependent CD (CDAI < 150, AND a
`prednimme dose of 15-40 mg/day or a budesrmide dose of 9mghlay for >
`8 weeks, AND a failed attempt to taper prednisone or budesanide within 8
`weeks) were enrolled into a 16 week study and randomized to one of two
`treatments: 1) CDP571 20 mg/kg at week 0 followed by 10 mg/kg at week
`8; 2) placebo at weeks 0 and 8. Predoisone was decreased from the week
`0 dose by 5 mg/week to a dose of 10 mg/day, and then by 2.5 mg/week
`until discontinuation. Budesonide was decreased from 9 mg/day to 6
`meduy for 3 weeks, 3 mg/day for 3 weeks, and then discontinued.
`5-Aminosalicylatee, patine antimemholites and methotremne were held
`constant at the pre-study dose. The primary outcome was defined as total
`steroid withdrawal without a flare of CD (increase in CDAI to > 220
`points). RESULTS: 39 patients received CDP571 and 32 received placebo:
`the demographic characteristics of the patients were not different in the two
`groups. At week 40, 17/39 (43.6%) of patients who received CDP571
`remained free of a disease flare as compered with only 7/32 (21.9 %) of
`thuse who received placebo (P = 0.049). CDP57I therapy was well
`tolerated. No severe infusion reactions were identified, Serious adverse
`events occurred in 12.5% of patients receiving placebo and 17.9% of those
`assigned to active treatment; the majority of these were disease related and
`none were attributed tee CDP571 therapy, Only one patient (2.6%) devel-
`oped detectable antibody to CDP57I. 6.7% of patients developed anti-
`dont-Fie-stranded DNA antibodies. No CILSC5 of lupus or lymphoma oc-
`curred. CONCLUSIONS: CDP57 I is an effective therapy which facilitates
`withdrawal of coniecisteroids in adults with chronic steroid dependent CD.
`Therapy with CDP571 is associated with a low incidence of adverse events.
`A low race of auto-antibody formation was mime and antibodies to
`CDP571 occurred infrequently.
`
`Ex. 1099 - Page 1
`
`
`
`Supplement to
`
`lutill8 • Nuniber 4 • Suppl 2
`Part 1 of 2
`
`...
`
` e
`
`Digest' e ease Week
`and the
`Olst Annual Meeting of the Amer n
`i
`Gastroenterologicai Association it
`May 21-24, 2000, SJn Dieg9, to
`
`Program of the Annual Meeting of the Amerk n
`astroenter.logical Association, the A erican i
`iv he Study of Liver Dise es, the
`Associa r: .
`Gastro.-Jr,r,- 4 * 6 Research Group, the' ociety fo
`Surge , , the Alimentary Tract, and the American
`Societ or Gastrointestinal Endoscopy
`r
`Abstracts of Paper SUbmitted to the American 4 1
`Gastroenterological Association
`i
`Abstracts of PapereSubmitted to the Anjerican (cid:9)
`Associa'on for le Study of Liver Diseases
`. i
`i
`o th Society fo
`61
`'q
`
`go
`
`11
`
`▪ Abstrac s of Paers Submi r (cid:9)
`- Surgery of the Mime itary (cid:9)
`
`Ex. 1099 - Page 2
`
`
`
`Notes
`
`VEVil (cid:9)
`
`F UECIT11.7.-
`
`_ (cid:9)
`
`6 9Clikq
`
`LtBRABY
`
`Ex. 1099 - Page 3
`
`
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