GASTROENTEROLOGY 1995;109:129-135
`
`Treatment of Crohn's Disease With Anti—Tumor Necrosis
`Factor Chimeric Monoclonal Antibody (cA2)
`
`HENDRIK M. VAN DULLEMEN,* SANDER J. H. VAN DEVENTER,'" DAAN W. HOMMES,*
`HANNIE A. BIJL,5 JAAP JANSEN,* GUIDO N. J. TYTGAT,* and JAMES WOODY
`*Department of Hepatogastroenterology and 'Center for Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, Academic
`Medical Center, Amsterdam, The Netherlands; and §Centocor Inc., Malvern, Pennsylvania
`
`Background & Aims: Increased concentrations of tumor
`necrosis factor (TNF), a potent proinflammatory cyto-
`kine, can be shown in the mucosa of patients with
`active Crohn's disease. Neutralization of TNF has been
`shown to decrease recruitment of inflammatory cells
`and granuloma formation in several animal models. The
`aim of this study was to investigate the safety and
`potential efficacy of an anti-TNF monoclonal antibody
`in the treatment of active Crohn's disease. Methods:
`Ten patients with active Crohn's disease that was unre-
`sponsive to therapy were administered a single infusion
`of an anti-TNF human/mouse chimeric monoclonal anti-
`body (cA2) in an open-label treatment protocol while
`the baseline anti-inflammatory therapy was continued.
`Results: Eight patients showed normalization of
`Crohn's Disease Activity Index scores and healing of
`ulcerations as judged by colonoscopy within 4 weeks
`after treatment. One patient had a perforation after
`colonoscopy and recovered completely after surgery.
`One elderly patient showed a poor response. The aver-
`age duration of response after a single infusion was 4
`months. No adverse experiences related to cA2 were
`observed. Conclusions: The results support the hypoth-
`esis that TNF is of major importance in the pathogene-
`sis of Crohn's disease. Treatment with cA2 was safe
`and may be useful in patients with Crohn's disease
`that is unresponsive to steroid treatment.
`
`Despite the availability of various immunosuppres-
`
`sive therapies, the treatment of patients with
`Crohn's disease that is unresponsive to steroids remains
`a clinical challenge. Substantial evidence implicates T-
`cell activation to be of pivotal importance in Crohn's
`disease.' Interference with T-cell activation, using
`cyclosporine, has been shown to benefit patients with
`acute disease,1•2 but long-term results have been disap-
`pointing.; In an attempt to more specifically target T
`cells, several investigators have recently studied the use
`of anti-CD4 monoclonal antibodies to deplete the CD4
`T-cell subpopularion, but only small numbers of patients
`have been studied.4'5
`
`Observations in experimental animals as well as pa-
`tients with infectious diseases have linked the synthesis
`of high amounts of tumor necrosis factor (TNF) to granu-
`lomatous inflammation, possibly through TNF-induced
`induction of intercellular adhesion molecule 1.6 TNF-a
`is thought to play an important role as a mediator of
`inflammation in Crohn's disease and is found in substan-
`tial amounts in the mucosa and stools of subjects with
`inflammatory bowel disease.' Moreover, in patients with
`Crohn's disease, a high number of mucosal as well as
`lamina propria cells has been shown to express TNF.8'9
`To test the hypothesis that TNF-a secretion in the
`gastrointestinal tract constitutes a major factor in the
`pathophysiology of Crohn's disease, we used a chimeric
`monoclonal antibody that is known to neutralize human
`TNF-cz. cA2 is a neutralizing anti-TNF chimeric mono-
`clonal antibodyl° that has been shown to inhibit TNF-
`induced interleukin 6 (IL-6) release and endothelial pro-
`coagulant and adhesion molecule expression. Studies in
`patients with rheumatoid arthritis"-`3 indicated that
`cA2 was an efficacious and potent anti-inflammatory
`agent in patients with a high disease activity. These
`properties made cA2 an appropriate candidate to study
`the potential clinical efficacy of functional blockade of
`TNF in Crohn's disease. Based on this evidence, a patient
`with severe Crohn's disease was treated with cA2 in our
`hospital, which resulted in a remarkable clinical im-
`provement." We therefore designed the present study
`in patients with steroid-unresponsive Crohn's disease to
`investigate the safety of anti-TNF therapy and to obtain
`preliminary results on its potential therapeutic effects.
`
`Materials and Methods
`
`Patient Selection and Study Design
`
`The open-label study was conducted at a single center.
`Approval for the study was granted by the local ethics commit-
`
`Abbreviations used in this paper: IL-6, interleukin 6; TNF. tumor
`necrosis factor.
`1995 by the American Gastroenterological Association
`0016-5085/95/$3.00
`
`Ex. 1103 - Page 1
`
`

`

`GASTROENTEROLOGY Vol. 109, No. 1
`
`130 VAN DULLEMEN ET AL.
`
`Table 1. Patient Characteristics
`
`Patient
`
`1
`2
`3
`
`4
`5
`
`6
`
`7
`8
`9
`
`Age
`ty4
`
`41
`25
`22
`
`20
`38
`
`Sex
`
`F
`F
`F
`
`F
`M
`
`26
`
`F
`
`40
`29
`64
`
`M
`F
`F
`
`Duration of
`Crohn's
`disease
`
`15
`8
`5
`
`3
`1.5
`
`1.5
`
`0.3
`4.5
`9
`
`CON
`
`210
`216
`205
`
`355
`275
`
`264
`
`285
`295
`273
`
`10
`
`31
`
`M
`
`13
`
`202
`
`Previous surgery
`
`Steroid
`treatment
`(mo)
`
`Prednisone
`dose
`(rng
`
`Extraintestinal
`manifestations
`
`180
`5
`60
`
`13
`5
`
`1
`
`4
`12
`1
`
`4
`
`12.5
`20
`20
`
`40 (cid:9)
`20
`
`7.5
`
`30
`30
`0
`
`20
`
`Pyoderma gangrenosum
`
`Arthritis
`
`Arthralgea
`
`Arthritis
`
`Subtotal colectomy with
`ileosigmoidal
`anastomasis
`
`Mesalazine (cid:9)
`
`Atattliolfrule
`
`Lacalizarion
`
`Yes
`Yes
`Yes
`
`Yes
`Yes
`
`No
`
`Yes
`Yes
`Yes
`
`Yes
`
`?••
`
`No (cid:9)
`Yes (cid:9)
`No (cid:9)
`
`No (cid:9)
`No (cid:9)
`
`Na (cid:9)
`
`No (cid:9)
`No (cid:9)
`No (cid:9)
`
`No (cid:9)
`
`Entire aeon
`Entire Colon
`Terminal ileum and
`colon
`Left Crew (cid:9)
`Terminal Oman and
`colon
`Temtinal thrill end
`proems' Coto
`Entire colon
`Entire colon
`Ariestomosit and
`rectum
`
`Terminal Ileum and
`coicei
`
`tee, and all patients gave their informed consent. Ten patients
`were recruited (mean age, 33.6 years; range, 20-64 years;
`mean duration of Crohn's disease, 6.1 years), each of whom
`had active Crohn's disease based on clinical evaluation (Crohn's
`Disease Activity Index [CDAII: mean, 258; range, 202-355)
`and endoscopic evaluation. Only patients with active inflam-
`mation of the colon and/or terminal ileum were included to
`enable endoscopic monitoring. Patient characteristics are sum-
`marized in Table 1. Treatment with prednisone, 20 mg or
`more for at least 2 weeks, had failed in all patients. Because
`of the side effects of prednisone treatment, 3 patients were
`already administered reduced doses of prednisone at entry into
`the study. However, the prednisone dose was not altered in
`the 2-week screening period before infusion of cA2. For the
`first 5 patients enrolled, the prednisone treatment was to be
`maintained at a stable dose throughout the 8-week study pe-
`riod; for the second 5 patients, prednisone treatment was to
`be tapered down if the patients responded well. Concomitant
`treatment with other immune-suppressive drugs was allowed,
`although patients who had started azathioprine treatment
`within 3 months before enrollment were excluded. Before and
`during the 8-week study period, no dietary alterations were
`made. Before treatment with monoclonal antibodies, other ex-
`clusion criteria consisted of a positive test result for human
`immunodeficiency virus and treatment that could potentially
`modulate TNF synthesis (e.g., pentoxifylline or plasmaphere-
`sis).
`
`Treatment
`
`Treatment consisted of a single intravenous infusion
`of the anti-TNF chimeric monoclonal antibody (cA2) at a dose
`of 10 mg/kg administered as a 2-hour infusion. The last 2
`patients were administered 20 mg/kg to evaluate the safety of
`a higher dose. cA2 is a chimeric monoclonal anti-TNF anti-
`body that is composed of the constant regions of the human
`immunoglobulin G1K coupled to the Fv region of a high-
`affinity neutralizing murine anti-human TNF-ct antibody
`(A2).'° The antibody was produced by Centocor Inc. (Malvern,
`
`PA) by continuous fermentation of a mouse myeloma cell line,
`which had been transfected with cloned complementary DNA
`coding for cA2 and was purified from culture supernatant by
`a series of steps involving column chromatography. The final
`vials contained a sterile, nonpyrogenic solution of either 5 or
`10 mg/mL of cA2 in 0.15 mol/L sodium chloride, 0.01 mol/
`L sodium phosphate (pH 7.2), and 0.01% polysorbate 80. The
`appropriate amount of cA2 was withdrawn through a 0.2-
`gmol/L low protein—binding sterile filter, diluted with 0.9
`molfL saline to a total volume of 300 mL, and administered
`intravenously over a period of 2 hours. Patients were admitted
`for a 24-hour period for the treatment. All drug therapies used
`for Crohn's disease were continued at the dose used at study
`entry for the entire study period, which extended 2 months.
`
`Assessments
`
`Blood pressure, temperature, and pulse were measured
`before infusion. Thirty-minute serial determinations were
`made after starting the infusion and were continued during a 4-
`hour period. Routine hematology, blood chemistry, and urinic
`analysis were performed before the infusion and at 24 and 72
`hours. Additional samples were drawn at weeks 2, 4, 6, and
`8. Videoendoscopy of the colon was performed 1 day before
`the infusion and at weeks 4 and 8. An endoscopic score as
`described by Mary and Modigliani15 was accessed for each
`colonoscopy. In addition, a subjective score was developed and
`assessed before treatment and at weeks 2, 4, 6, and 8. Excellent
`response was defined as 1, good response as 2, fair response as
`3, no response as 4, and worsening as 5. Patients used a daily
`diary system before and during the 8-week study period for
`assessment of the CDAI. CDAI scores were determined within
`1 week before the infusion and after infusion on weeks 2, 4,
`6, and 8.
`C-reactive protein and IL-6 concentrations in serum were
`assessed before the infusion and at weeks 2, 4, 6, and 8. Serum
`IL-6 level was assessed using an enzyme-linked immunosorbent
`assay for human IL-6 with a baseline of 2-4 pg/mL (Central
`Laboratory of the Blood Transfusion Services, Amsterdam, The
`
`Ex. 1103 - Page 2
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`July 1995
`
`ANTI-TNF IN CROHN'S DISEASE 131
`
`Clinical Response
`
`One patient (patient 7) was excluded from the
`efficacy evaluation because the CDAI could not be evalu-
`ated and follow-up colonoscopies were not performed.
`This patient was administered cA2 after a missed perfora-
`tion of the sigmoid during the screening colonoscopy.
`After surgery performed 2 weeks after the infusion, he
`completely recovered. The resection specimen showed no
`remaining ulcers in the sigmoid colon, whereas numerous
`ulcers had been found at the baseline colonoscopy.
`Of the 9 remaining patients, 8 reported improvement
`of subjective symptoms within 1 week after treatment. Four
`weeks after infusion, these 8 patients scored "excellent or
`good response to treatment" on the subjective scoring list.
`They all noted a substantial reduction of stool frequency.
`In the 9 evaluable patients, the mean CDAI was 257
`before treatment and decreased to 114 at 2 weeks, 79 at
`4 weeks, 61 at 6 weeks, and 69 at week 8 (Figure 1).
`Table 2 shows the hemoglobin level and weight of each
`patient during the 8-week period.
`
`Videoendoscopy
`
`Videoendoscopy after 4 weeks showed a (near)
`complete healing of all previously observed ulcerations
`(Figure 2). Figure 3 shows the endoscopic response as
`expressed by the Modigliani score.
`
`Time to Relapse
`
`At the week 8 evaluation, one of the responders
`(patient 1) did not fulfill the remission criteria (CDAI
`of <150) any more, although it took approximately 4
`months before the disease activity was back to the pre-
`treatment level. The other 7 responders were still in
`remission at week 8. These patients were followed up
`clinically and had a relapse after approximately 3 months
`(patient 2); 4 months (patients 3, 5, and 6); 4 and 5
`
`0 (cid:9)
`
`2 (cid:9)
`4
`weeks after infusion
`
`6
`
`8
`
`Figure 1. CDAI after infusion of cA2 (n = 9). Values represent means,
`bars represent the 25th and 75th percentiles, and error bars indicate
`the 5th and 95th percentiles (P < 0.0001).
`
`Netherlands). The soluble TNF receptors P55 and P75 in the
`serum were assessed before infusion and at 2, 4, and 8 weeks.
`Soluble TNF receptors P55 and P75 were measured with enzyme-
`linked immunologic binding assays as previously described.16
`
`Statistical Analysis
`Results of the CDAI, Modigliani score, C-reactive pro-
`tein, erythrocyte sedimentation rate, IL-6, and soluble TNF
`receptor are presented as box plots. The significance of changes
`of the variables in time was calculated using SPSS for Windows
`(SPSS Inc., Chicago, IL) by means of one-way analysis of vari-
`ance (ANOVA). a was set at 0.05 (two-sided).
`
`Results
`
`Side Effects of cA2
`
`Infusion of cA2 was well tolerated. All patients felt
`well and did not experience side effects. No febrile or allergic
`reactions were observed. During and after infusion, there was
`no instability in blood pressure or heart rate. No changes were
`encountered in routine biochemistry and urinary analysis after
`treatment. No adverse events related ro cA2 were observed.
`
`Table 2. Hemoglobin Level and Weight After Infusion of cA2
`
`Preinfusion
`
`Week 2
`
`Week 4
`
`Week 6
`
`Week 8
`
`Patient
`
`Hb
`(mmol/L)
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`
`6.7
`8.4
`8.8
`8.1
`8.8
`7.7
`6.3
`6.8
`8.6
`7.4
`
`Hb. hemoglobin.
`
`Wt
`(kg)
`
`69
`84
`79
`68
`58
`64
`101
`54
`78
`54
`
`Hb
`(mmol/L)
`
`7.3
`8.1
`8.1
`8.4
`8.1
`7.7
`
`7.5
`8.9
`8.3
`
`Wt
`(kg)
`
`70
`85
`81
`68
`61
`64
`
`56
`75
`54
`
`Hb
`(mmol/L)
`
`7.1
`7.8
`8.4
`7.6
`7.3
`7.4
`
`7.4
`8.6
`9.6
`
`Wt
`(kg)
`
`71
`86
`80
`69
`67
`63
`
`56
`75
`60
`
`Hb
`(mmo!/L)
`
`Wt
`(kg)
`
`Hb
`(mmol/L)
`
`7.4
`7.9
`7.9
`8.0
`7.9
`8.4
`
`7.7
`9.2
`8.9
`
`73
`87
`81
`70
`63
`63
`
`57
`75
`62
`
`7.1
`7.5
`8.5
`7.8
`7.8
`8.2
`
`7.2
`8.9
`8.6
`
`Wt
`(kg)
`
`72
`87
`81
`70
`66
`61
`
`56
`74
`62
`
`Ex. 1103 - Page 3
`
`(cid:9)
`(cid:9)
`

`

`132 VAN DULLEMEN ET AL.
`
`GASTROENTEROLOGY Vol. 109, No. 1
`
`-1"1111111
`
`A
`
`Figure 2. Healing of colonic ulcerations in 2 patients (patients 1 and 8) after treatment with cA2. (A and C) At enrollment and (3 and D) 4
`weeks after infusion of cA2. Photographs were obtained from videotapes, allowing comparison of exactly the same location.
`
`A
`
`months (patient 10); 5 months (patient 8); and 6 months
`(patient 4). In the second group of 5 patients, there were
`3 responders (patients 6, 8, and 10); in all 3 of these
`patients, it was possible to discontinue the corticosteroid
`treatment within the 8-week study period without any
`adverse effect on disease activity or duration of response.
`
`Extraintestinal Manifestations
`
`The extraintestinal manifestations of Crohn's disease
`responded substantially after treatment with cA2. The pyo-
`derma gangrenosum in patient 2 improved substantially
`after treatment but did not vanish completely. The arthritis
`and/or arthralgia complaints, if present at baseline, vanished
`in all patients after treatment. Of further interest is the
`
`long-standing history (approximately 20 years) of acne in
`patient 5, which also vanished after treatment with cA2.
`In contrast to the other subjects, 1 elderly patient
`(patient 9) showed only partial clinical improvement.
`The CDAI decreased from 273 to 175 (week 6). Remark-
`able healing of colonic ulceration was observed in all
`
`patients except in this patient in whom only the ulcers
`seen at the ileocolonic anastomosis had healed, whereas
`the ulcers in the rectum persisted.
`
`Laboratory Variables
`
`The C-reactive protein levels rapidly decreased in
`the 9 evaluable patients (Figure 4), reaching normal lev-
`els within 2 weeks. A less dramatic reduction of the
`
`Ex. 1103 - Page 4
`
`

`

`ANTI-TNF IN CROHN'S DISEASE 133
`
`70-
`
`61:1
`
`504
`
`40.!
`
`E
`w 30-
`u)
`
`20-
`
`10.
`0. —N =
`
`
`
`0
`
`2 (cid:9)
`
`4
`
`6
`
`8
`
`weeks after infusion
`
`Figure 5. Erythrocyte sedimentation rate after cA2 infusion (n = 9).
`Values represent means, bars represent the 25th and 75th percen-
`tiles, and error bars indicate the 5th and 95th percentiles (P = 0.34).
`
`July 1995
`
`30
`
`20
`
`0
`
`modigliani score
`
`0 (cid:9)
`
`4 (cid:9)
`weeks after infusion
`
`8
`
`Figure 3. Endoscopic response as expressed by Modigliani score at
`baseline, 4 weeks, and 8 weeks (n = 9). Values represent means,
`bars represent the 25th and 75th percentiles, and error bars indicate
`the 5th and 95th percentiles (P < 0.002).
`
`erythrocyte sedimentation rate was noted. However, 4
`weeks after the infusion of cA2, the erythrocyte sedimen-
`tation rate had normalized in all subjects (Figure 5).
`Finally, although the circulating levels of IL-6 were
`found to be <10 pg/ml, in all but 2 patients at enroll-
`ment, a decrease was noted at 2 weeks after infusion
`(Figure 6). The circulating concentrations of the two
`soluble TNF receptors were not found to be elevated at
`the start of the study, and no significant changes were
`observed during the study (Figures 7 and 8).
`Discussion
`The results of this study support the hypothesis
`that TNF-a is a major factor in the pathophysiology of
`Crohn's disease. Although the present study is small and
`uncontrolled, we observed complete clinical as well as
`endoscopic remissions in all but 1 of the evaluable pa-
`tients with steroid-unresponsive Crohn's disease after a
`single infusion of the anti-TNF monoclonal antibody
`cA2. Although these results may have been considerably
`
`biased because of the small size and the nonblinded de-
`sign of the study, several observations indicate that the
`clinical response resulted from an anti-inflammatory ac-
`tivity of the infused monoclonal antibody. After the infu-
`sion, C-reactive protein levels decreased in all patients,
`rapidly reaching normal values. Furthermore, anti-TNF
`therapy caused a near complete healing of all documented
`endoscopic abnormalities evaluated at 4 weeks. Finally,
`despite continued treatment with prednisone, 5 patients
`had a relapse at 6 weeks to 6 months after cA2 infusion.
`The remarkable clinical benefit of a single infusion
`of cA2 was obtained in the absence of any toxicity. In
`particular, the infusion caused no hemodynamic instabil-
`ity, fever, or allergic symptoms, and no significant
`changes in routine blood biochemistry, urinary analysis,
`and hematologic parameters occurred in the study period.
`Although this study was not designed to evaluate the
`long-term efficacy of anti-TNF treatment in Crohn's dis-
`ease, the present data allow some prediction on the dura-
`
`20
`
`15.
`
`S
`-a, 10,
`
`cp
`
`0
`
`2 (cid:9)
`
`4
`weeks after infusion
`
`6
`
`8
`
`0 (cid:9)
`
`2 (cid:9)
`
`4
`
`6 (cid:9)
`
`8
`
`weeks after infusion
`
`Figure 4. Serum C-reactive protein levels after cA2 infusion (n = 9).
`Values represent means, bars represent the 25th and 75th percen-
`tiles, and error bars indicate the 5th and 95th percentiles (P < 0.001).
`
`Figure 6. Serum IL-6 levels after cA2 infusion (n = 9). Values repre-
`sent means, bars represent the 25th and 75th percentiles, and error
`bars indicate the 5th and 95th percentiles (P =. 0.49).
`
`Ex. 1103 - Page 5
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`134 VAN DULLEMEN ET AL.
`
`GASTROENTEROLOGY Vol. 109, No. 1
`
`4
`
`3
`
`sTNFR p75 (ng/ml)
`
`2
`
`sTNFR p55 (ng/m1)
`
`r (cid:9)
`2 (cid:9)
`
`ra
`4
`
`weeks after infusion
`
`9
`
`8
`
`4
`2 (cid:9)
`weeks after infusion
`
`6 (cid:9)
`
`8
`
`Figure 7. Serum concentration of the soluble TNF receptor P55 after
`infusion of cA2 (n = 9). Values represent means, bars represent the
`25th and 75th percentiles, and error bars indicate the 5th and 95th
`percentiles. No significant changes were observed during the study
`(P = 0.72).
`
`Figure 8. Serum concentration of the soluble TNF receptor P75 after
`infusion of cA2 (n = 9). Values represent means, bars represent the
`25th and 75th percentiles, and error bars Indicate the 5th and 95th
`percentiles. No significant changes were observed during the study
`(P = 0.68).
`
`tion of a response to a single infusion. Seven patients
`were in a complete clinical remission at 8 weeks after
`infusion; in 1 patient (patient 1), the C-reactive protein
`level was already increasing at that time point, and the
`patient was classified as having a relapse, although she
`was clinically better than before infusion. Endoscopic
`examination showed renewed activity with the return of
`ulceration at the site of previous ulceration. Hence, we
`estimate the duration of remission of Crohn's disease after
`a single anti-TNF treatment to last about 4 months.
`The mechanism of action of cA2 in Crohn's disease
`remains unknown. Because TNF remains largely com-
`partmentalized within the mucosa in Crohn's disease, the
`observed decrease in C-reactive protein levels probably
`resulted from decrease in serum IL-6 levels. This observa-
`tion therefore extends the known regulatory role of TNF
`for IL-6 production in endotoxemia to immunologically
`induced inflammation. It is likely that the effects of anti-
`TNF treatment resulted from neutralization of bioactive
`TNF in the mucosa, where it could have interfered with
`the known ability of TNF to facilitate recruitment of
`inflammatory cells. Alternatively, cA2 may have neutral-
`ized membrane-bound TNF, which is thought to have a
`potential role in T-cell activation. The latter view is
`supported by the long duration of clinical responses after
`a single infusion. It is therefore more likely that anti-
`TNF caused immunomodulatory effects rather than sim-
`ply neutralizing TNF released from source cells.
`The results of anti-TNF treatment of Crohn's disease
`are comparable with the outcome of a recent study in
`patients with rheumatoid arthritis. Treatment of active
`rheumatoid arthritis with cA2 at a dose of 20 mg/kg in
`an open phase I/II trial lasting 8 weeks was safe and
`well tolerated and resulted in significant clinical and
`
`laboratory improvements, including reductions of eryth-
`rocyte sedimentation rate and C-reactive protein."
`In conclusion, this study indicates that a single infu-
`sion of an anti-TNF monoclonal antibody (cA2) resulted
`in remarkable clinical improvement in 8 of 10 consecu-
`tive patients with steroid-unresponsive Crohn's disease.
`Treatment with cA2 caused no adverse events or side
`effects. In 8 patients, the CDAI score normalized within
`4 weeks after treatment. In addition, in all patients, near
`complete healing of previously present ulcerations was
`noted at videoendoscopy. The average duration of re-
`sponse after a single infusion was 4 months. The results
`indicate that anti-TNF antibody therapy has potential
`in steroid-unresponsive Crohn's disease. Controlled stud-
`ies to further evaluate the clinical efficacy of cA2 in
`Crohn's disease have been initiated.
`
`References
`
`1. Brynskov J, Freund L, Rasmussen SN, Lauritsen K. Schaffalitzky-
`de-Muckadell 0, Williams N, MacDonald AS, Tanton R, Molina F,
`Campanini MC, Bianchi P, Ranzi T. Quarto-di-Palo F, Malchow-
`Moller A, Thomsen 00, Tage-Jensen U. Binder V, Riss P. A pla-
`cebo-controlled, double-blind, randomized trial of cyclosponn
`therapy in active chronic Crohn's disease. New Engl J Med
`1989; 321:845-850.
`2. Brynskov J, Tvede N. Plasma interleukin-2 and a soluble/shed
`interleukin-2 receptor in serum of patients with Crohn's disease.
`Effect of cyclosporin. Gut 1990;31:795-799.
`3. Feagan BG, McDonald JWD, Rochon J, Laupacis A, Fedorak RN,
`Kinnear D, Saibil F. Groll A, Archambault A, Gillies R, Valberg B,
`Irvine El. Low dose cyclosporine for the treatment of Crohn's
`disease. N Engl J Med 1994;330:1.846-1851.
`4. Stronkhorst A, Tytgat GNJ, van Deventer SJH. CD4 antibody treat-
`ment in Crohn's disease. Scand J Gastroenterol 1992;27
`(Suppl):61-65.
`5. Deusch K, Mauthe B, Reiter C, Riethmuller G, Classen M. CD4-
`antibody treatment of inflammatory bowel disease: one-year fel-
`low up. Gastroenterology 1993:104:A691.
`6. Lukacs NW, Chensue SW, Strieter R, Warmington K, Kunkel SL.
`
`Ex. 1103 - Page 6
`
`

`

`July 1995
`
`ANTI-TNF IN CROHN'S DISEASE 135
`
`Inflammatory granuloma formation is mediated by TNF-alpha-
`inducible intercellular adhesion molecule-1. J Immunol 1994;
`152:5883-5889.
`7. Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT.
`Tumour necrosis factor alpha in stool as a marker of intestinal
`inflammation. Lancet 1992;339:89-91.
`8. MacDonald TT, Hutchings P, Choy M, Murch S, Cooke A. Tumour
`necrosis factor-alpha and interferon-gamma production mea-
`sured at the single cell level in normal and inflamed human intes-
`tine. Clin Exp Immunol 1990;81:301-305.
`9. Breese EJ, Michie CA, Nicholls SW, Murch SH, Williams CB, Domi-
`zio PWS, MacDonald TT. Tumor necrosis factor alpha-producing
`cells in the intestinal mucosa of children with inflammatory bowel
`disease. Gastroenterology 1994;106:1455-1466.
`10. Knight DM, Trinh H, Le J, et al. Construction and initial characteri-
`sation of a mouse-human anti-TNF antibody. Mol Immunol
`1993; 30:1443-1453.
`11. Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis
`P, Brennan FM, Walker1, BijI H, Ghrayeb J, Woody 1N. Treatment
`of rheumatoid arthritis with chimeric monoclonal antibodies to
`tumour necrosis factor a. Arthritis Rheum 1993;36:1681-
`1690.
`12. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen
`JS, Leeb B, Breedveld FC, Macfarlane JD, BijI H, Woody JN. Ran-
`
`domised double-blind comparison of chimeric monoclonal anti-
`body to tumour necrosis factor alpha (cA2) versus placebo in
`rheumatoid arthritis. Lancet 1994;344:1105-1110.
`13. Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Bijl H,
`Woody 1N. Repeated therapy with monoclonal antibody to tumour
`necrosis factor alpha (cA2) in patients with rheumatoid arthritis.
`Lancet 1994; 344:1125-1127.
`14. Derkx B, Taminiau, Radema S, Stronkhorst A, Wortel C, Tytgat
`GNJ, van Deventer SJH. Tumour necrosis factor antibody treat-
`ment in Crohn's disease. Lancet 1993;342:173-174.
`15. Mary JY, Modigliani R. Development and validation of an endo-
`scopic index of the severity for Crohn's disease: a prospective
`multi centre study. Gut 1989;30:983-989.
`16. Godfried MH, van der Poll T, Jansen J, Romijn JA, Eeftinck Schat-
`tenkerk JKM, Endert E, van Deventer SJH, Sauerwein HP. Soluble
`receptors for tumour necrosis factor: a putative marker of dis-
`ease progression in HIV infection. AIDS 1993;7:33-36.
`
`Received October 13, 1994. Accepted February 17, 1995.
`Address requests for reprints to: Hendrik M. van Dullemen, M.D.,
`Department of Hepatogastroenterology, Academic Medical Center,
`Meibergdreef 9, 1105 AZ Amsterdam Zuidoost, The Netherlands.
`Fax: (31) 20-691-7033.
`
`Ex. 1103 - Page 7
`
`(cid:9)
`

`

`Omeprazole
`(n=465)
`Headache
`6.9 (2.4)
`Diarrhea
`3.0 (1.9)
`ANbaudsoeaminal Pain 2.4 (0.4)
`2.2 (0.9)
`1.9
`1.5 (0.6)
`1.5 (0.4)
`1.5 (1.1)
`1.1 (0.9)
`1.1
`1.1 (0.2)
`1.1
`
`URi
`Dizziness
`Vomiting
`Rash
`Constipation
`Cough
`Asthenia
`Back Pain
`
`Placebo
`(n=64)
`6.3
`3.1 (1.6)
`3.1
`3.1
`1.6
`0.0
`4.7
`0.0
`0.0
`0.0
`1.6 (1.6)
`0.0
`
`Raniticline
`(n=195)
`7.7 (2.6)
`2.1 (0.5)
`2.1
`4
`.1 (0.5)
`2.6
`2.6 (1.0)
`t5 (0.5)
`0.0
`0.0
`1.5
`1.5 (1.0)
`0.5
`
`Additional adverse experiences occurring In <1% of patients
`or subjects in domestic and/or international trials, or occurring
`since the drug was marketed, are shown below, listed by
`body system. In many Instances, the relationship to
`PRILOSEC' (orneprazole) was unclear.
`Body as a 1.4910)e: Fever, pain, fatigue, malaise, abdominal
`swelling. Cardiovascular: Chest pain or angina, tachycardia,
`bradycardia, palpitation, elevated blood pressure, peripheral
`edema. Gastrointestinal: Pancreatitis (some fatal), anorexia,
`irritable colon, flatulence, fecal discoloration, esophageal
`candidiasis, mucosal atrophy of the tongue, dry mouth.
`Hepatic: Mild and, rarely, marked elevations of liver func-
`tion tests (ALT (SGPT), AST (500T), -y-glutamyl transpepti-
`dase, alkaline phosphatase, and bilirubin (jaundice)). In rare
`instances, overt liver- disease has occurred, including hepa-
`tocellular, cholestatic, or mixed hepatitis, liver necrosis
`(some fatal), hepatic failure (some fatal), and hepatic
`encephalopathy. Metabolic/ Nutritional: Hypoglycemia,
`weight gain. Musculoskeletal: Muscle cramps, myalgia,
`muscle weakness, joint pain, leg pain. Nervous
`System/Psychiatric: Psychic disturbances including
`depression, aggression. hallucinations, confusion, Insom-
`nia, nervousness, tremors, apathy, somnolence, anxiety,
`dream abnormalities; vertigo; paresthesra: remitacial dys-
`esthesia. Respiratory: Epistaxis, pharyngeal pain. Skin: Rash
`and, very rarely, cases of severe generalized skin reactions
`including toxic epidermal necrohysis (TEN; some fatal),
`Stevens-Johnson syndrome. and erythema multiforme
`(some severe); skin inflammation, urticaria, angioedema,
`pruritus, alopecia, dry skin, hyperhidrosis. Special Senses:
`Tinnitus, taste perversion. Urogenital: Interstitial nephritis
`(some with positive rechallenge), urinary tract infection,
`microscopic pyuria. urinary frequency, elevated serum ere-
`atinine, proteinuria, hernatuha, glycosuria, testicular pain,
`gynecomastia. Hematologic: Rare instances of pancytope-
`nia. agranulocytosis (some fatal), thrombocylopenia, neu-
`tropenia, anemia. leucocytosis, and hemolytic anemia have
`been reported.
`The incidence of clinical adverse experiences in patients
`greater than 65 years of age was similar to that in patients
`65 years of age or less.
`OVERDOSAGE
`There is no experience to date with deliberate overdosage.
`Dosages of up to 360 mg/day have been well tolerated.
`No specific antidote is known. Omeprazole Is extensively
`protein bound and is, therefore, not readily dialyzable. In the
`event of overdosage, treatment should be symptomatic
`and supportive.
`DOSAGE AND ADMINISTRATION
`Short-Term Treatment of Active Duodenal Ulcer: The
`recommended adult oral dose is 20 mg once daily. Most
`patients heal within 4 weeks, Some patients may require an
`additional 4 weeks of therapy. (See INDICATIONS AND USAGE.)
`Erosive Esophagifis or Poorly Responsive
`Gastroesophageal Reflux Disease (GERD): The recom-
`mended adult oral dose is 20 mg daily for 4 to 8 weeks.
`(See INDICATIONS AND USAGE.)
`Pathological Hypersecretory Conditions: The dosage
`of PRILOSEC in patients with pathologIcal hypersecretory
`conditions varies with the individual patient. The recom-
`mended adult oral starting dose is 60 mg once a day. Doses
`should be adjusted to individual patient needs and should
`continue for as long as clinically indicated. Doses up to 120
`mg ti.d. have been administered, Daily dosages of greater
`d poses..
`than 80 mg should be administered in rcil
`No dosage adjustment is necessisyffapiheMe 17;rariienal
`impairment, hepatic dysfunction, or for the elderly.
`Dist by:
`
`e=
`
`ic 1 1995
`ASTR (cid:9)
`Wayne, 41.0.1,11614, a medicine
`Manufactured by:
`MERCK & CO., INC.,
`West Point, PA 19486, USA
`
`PRI12
`February 1995 (cid:9)
`1146. 3. Bell NJV, Burget D. Howden CW, et al. Appropriate
`acid suppression for the management of gastro-
`oesophageal reflux disease. Digestion. 1992;51(suppl 1):59-
`67. 4 Data on file, DA-PRI01.
`
`interaction with theophylline or propranolol was found,
`there have been clinical reports of interaction with other
`drugs metabolized via the cytochrome P-450 system (e.g.,
`cyclosporine, disulfiram, benzodiazepines). Patients should
`be monitored to determine if it Is necessary to adjust the
`dosage of these drugs when taken concomitantly with
`PRILOSEC (omeprazole).
`In clinical trials, antacids were used concomitantly with
`administration of PRILOSEC.
`
`Carcinogenesis, Mutagenesis, impairment of Fertility:
`In two 24-month carcinogenicity studies In rats, omeprazole
`at daily doses of 1.7, 3.4, 13.8, 44. and 140.8 mg/kg/day
`(approximately 4 to 352 times the human dose, based on
`a patient weight of 50 kg and a human dose of 20 mg) pro-
`duced gastric ECL cell carclnoids in a dose-related manner
`in both male and female rats; the incidence of this effect
`was markedly higher in female rats, which had higher
`blood levels of omeprazole. Gastric carcincrds seldom
`occur in the untreated rat. In addition, ECL cell hyperplasia
`was present in all treated groups of both sexes. In one of
`these studies, female rats were treated with 13.8 mg/kg/day
`omeprazole (approximately 35 times the human dose) for 1
`year, then followed for an additional year without the drug.
`No carcinoids were seen in these rats. An increased inci-
`dence of treatment-related ECL cell hyperplasia was
`observed at the end of 1 year (94% treated vs 10% control).
`By the second year, the diffe