WI CL71.51,3
`V.I0 (cid:9)
`NO.S (cid:9)
`103
`C.01 -------- SEO: lAW0d9772
`TI: lilo0PUGS
`
`11/ 19/ 98
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`TM
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`Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy
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`November 1998, Vol. 10, No. 5 (pp. 341-422)
`ISSN: 1173-8804
`
`Adis Drug Evaluation
`Infliximab
`
`Leading Article
`Immunology of CpG DNA
`
`Disease Management
`Pancreas ransplantation for Diabetes Mellitus
`
`Review Articles
`Effects of MMF on Clinical Transplantation
`Emerging Pharmacotherapy for Pancreatitis
`
`Original Research Article
`Ribosomal Immunotherapy of Respiratory Tract Infections
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`111.
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`Ex. 1090 - Page 1
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`

`

`Vol. 10, No. 5, 1998
`
`Contents
`
`Leading Article
`
`Disease
`Management
`
`Review Articles
`
`The CpG Motif: Implications for
`Clinical Immunology
`AM Krieg
`
`Pancreas Transplantation for Diabetes Mellitus:
`A Guide to Recipient Selection and
`Optimum Immunosuppression
`RJ Stratta, RR Alloway
`
`341-346
`
`347-357
`
`Acute Pancreatitis: An Overview of
`Emerging Pharmacotherapy
`K Sargen, AN Kingsnorth
`Mycophenolate Mofetil: Effects on
`Clinical Transplantation
`CD Holt, TM Sievers, RM Ghobrial,
`SJ Rossi, IA Goss, SV McDiarmid
`
`Immunological Disorders 359-371
`
`Immunology-Based 373-384
`Agents
`
`Original Research
`Article
`
`Economic Evaluation of Ribosomal
`Immunotherapy in Patients with Chronic Ear,
`Nose and Throat and Respiratory Tract Infections:
`Results for Italy
`K Banz, AM Thomas, D Olivieri
`
`Adis Drug
`Evaluation
`
`Infliximab: A Review of its Use in Crohn's Disease
`and Rheumatoid Arthritis
`SV Onrust, HM Lamb
`
`385-396
`
`397-422
`
`BioDrugs is indexed in Chemical Abstracts, EMBASE/Exceruta Medial, Current Contents/ Clinical Medicine, Science Citation Index''',
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`This m ata ri a I was, gar.
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`Ex. 1090 - Page 2
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`

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`vr9: Died
`Ti= (cid:9)
`a: 7^ NP,1Eni Tavbe
`Subj, 77 7_17- (cid:9)
`t Laws
`
`Ex. 1090 - Page 3
`
`

`

`ADIS DRUG EVALUATION
`
`8IoDrugs 1998 Nov; 10 (5): 397-422
`1173-8804/98/0011-0397/$13.00/0
`
`Adis International Limited. All rights reserved.
`
`Infliximab
`A Review of its Use in Crohn's Disease and
`Rheumatoid Arthritis
`
`Susan V Onrust and Harriet M. Lamb
`Adis International Limited, Auckland, New Zealand
`
`Various sections of the manuscript reviewed by:
`E. Choy, Rheumatology Unit, Department of Medicine, King's College, London, England; A. Eigler,
`Medizinische Klinik, Klinikum Innestadt der Ludwig-Maximilians-Universitat, Munich, Germany; S.
`Endres, Medizinische Klinik, Klinikum Innestadt der Ludwig-Maximilians-Universitat, Munich, Germany;
`B.I. Korelitz, Department of Medicine, Lenox Hill Hospital, New York, New York, USA; D.E. Levy,
`Department of Pathology, New York University Medical Center, New York, New York, USA; R. Maini,
`Kennedy Institute of Rheumatology, London, England; R. Modigliani, Service d'Hepato Gastro-Enterologie,
`Hopital Saint-Louis, Paris, France; H.E. Paulus, Division of Rheumatology, Department of Medicine,
`University of California, Los Angeles, California, USA; M.Robinson, Oklahoma Foundation for Digestive
`Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; S. van Deventer,
`Academisch Medisch Centrum, Amsterdam, The Netherlands; J. Vilcek, Department of Microbiology, New
`York University Medical Center, New York, New York, USA.
`
`Data Selection
`Sources: Medical literature published in any language since 1966 on infliximab, identified using AdisBase (a proprietary database of Adis
`International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published
`articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
`Search strategy: AdisBase search terms were 'infliximab', 'centnf', 'ca2', 'anti-tnf-alpha', 'monoclonal', 'chimeric', 'antibody', 'Crohn's
`disease', 'ulcerative colitis' and 'rheumatoid arthritis'. Medline and EMBASE search terms were 'infliximab', 'centnf', 'anti-tnf', 'monoclonal',
`'antibody', 'anti-tnf-alpha', 'rheumatoid arthritis', 'inflammatory bowel diseases' and 'colitis'. Searches were last updated 14 October 1998.
`Selection: Studies in patients with Crohn's disease or rheumatoid arthritis who received infliximab. Inclusion of studies was based mainly
`on the methods section of the trials. Relevant pharmacodynamic and pharmacokinetic data are also included.
`Index terms: Infliximab, tumour necrosis factor-a, Crohn's disease, rheumatoid arthritis, pharmacokinetics, pharmacodynamics, therapeutic
`use, tolerability.
`
`Contents
`
`Summary
`1. Introduction (cid:9)
`2. Pharmacodynamic Properties (cid:9)
`2.1 (cid:9) Mechanism of Action
`2.1.1 Effects on TNFa-Regulated Factors (cid:9)
`2.1.2 Effects on Leucocyte Recruitment (cid:9)
`2.1.3 Effects on Peripheral Leucocytes (cid:9)
`2.2 Immunoglobulin Responses (cid:9)
`2.2.1 Anti-Inflixlmab Antibodies
`2,2.2 Antl-Double-Stranded DNA Antibodies (cid:9)
`3. Pharmacokinetic Properties
`4. Clinical Use in Crohn's Disease (cid:9)
`4.1 Single Infusions
`
`This mete. a I
`ettka. L'
`
`z : "pied
`Ey he
`
` 398
` 400
` 401
` 401
` 401
` 404
` 404
` 405
` 405
` 406
` 407
` 408
` 408
`
`Ex. 1090 - Page 4
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`398
`
`Onntst & Lamb
`
`5.
`
`4.1.1 Clinical Response Rate (cid:9)
`4.1.2 Onset and Duration of Response (cid:9)
`4,2 Multiple Infusions (cid:9)
`4.3 Effects on Fistulae (cid:9)
`Clinical Potential in Rheumatoid Arthritis
`
`5.1 single Infusions
`5.1.1 Clinical Response Rate
`5.1.2 Onset and Duration of Response (cid:9)
`
`5,2 Multiple Infusions (cid:9)
`5,3 Effect of Concurrent Methotrexate
`
`6. Tolerability (cid:9)
`
`6.1 Acute Infusion-Related Events
`6.2 Infection (cid:9)
`
`6.3 Other Events (cid:9)
`
`7, Dosage and Administration
`8. Place of Infliximab in the Management of Crohn's Disease and
`Rheumatoid Arthritis (cid:9)
`
` 408
` 410
` 410
` 411
`411
`412
`412
` 412
`412
`414
`415
`415
`415
`416
`416
`
` 417
`
`Summary
`Abstract
`
`Pharmacodynamic (cid:9)
`Properties (cid:9)
`
`Infliximab is a chimaeric monoclonal antibody which binds to and inhibits the
`activity of tumour necrosis factor-a (TNFa), a cytokine which is involved in the
`development of both Crohn's disease and rheumatoid arthritis. In patients with
`treatment-resistant Crohn's disease, infliximab was significantly more effective
`than placebo in the relief of symptoms. 50 to 89% of patients responded to in-
`fliximab and most of them also achieved remission. Patients showed signs of
`relapse 8 to 12 weeks after a single infusion but responded to additional infusions
`of the drug. Infliximab was also effective in closing the fistulae in 68% of patients
`with fistulising Crohn's disease; the response rate with placebo was 26%.
`Infliximab achieved a clinical response in 44 to 81% of patients with refractory
`rheumatoid arthritis. Following a single infusion, symptom recurrence was evi-
`dent after 6 to 12 weeks, but subsequent infusions re-established a clinical re-
`sponse. Concurrent methotrexate appeared to prolong the effects of infliximab in
`this patient group.
`Anti-infliximab and anti-double-stranded DNA antibodies developed in some
`patients, particularly those who received multiple infusions of infliximab. Acute
`adverse events consistent with hypersensitivity occurred in some patients who
`received multiple infusions of infliximab. Infection occurred slightly more fre-
`quently with infliximab than with placebo.
`Conclusions: Inflixirnab appears to be an effective therapy for patients with
`treatment-resistant or fistulising Crohn's disease or refractory rheumatoid arthri-
`tis. The tolerability, long term efficacy and optimal dosage regimen need to be
`further defined in comparative trials before the full potential of infliximab is
`realised in these patients.
`Tumour necrosis factor-a (TNFa) is present at elevated levels in inflamed tissues
`and is thought to play a central role in the pathogenesis of Crohn's disease and
`rheumatoid arthritis. Infliximab is a mouse-human chimaeric monoclonal anti-
`body which binds to and blocks the function of human TNFa. Consistent with
`blockade of TNFa, intravenous infliximab resulted in reduced expression of
`TNFa-regulated chemokines, endothelial adhesion molecules and interleukins in
`
`,e Adis International Limited. All rights reserved. (cid:9)
`
`BioDrugs 1998 Nov: 10 (5)
`
`THE
`
`Suc,jc.c
`
`Ex. 1090 - Page 5
`
`(cid:9)
`(cid:9)
`

`

`Infliximab: A Review (cid:9)
`
`399
`
`patients with Crohn's disease or rheumatoid arthritis. A 25 to 50% decrease in
`peripheral rnonocyte counts was observed in some patients who received in-
`fliximab, but resolved within a few weeks.
`Patients who received multiple infusions of infliximab were more likely to
`develop anti-infliximab antibodies than those who received single infusions, but
`concurrent methotrexate or higher doses of infliximab markedly reduced the anti-
`infliximab response. Anti-double-stranded DNA (anti-dsDNA) antibodies also
`developed in patients more frequently after multiple than after single infusions
`of infliximab.
`
`Serum infliximab concentrations increased in proportion with higher doses, and
`the median volume of distribution was 3.0 L with infliximab 5 mg/kg. Eight weeks
`after patients received infusions of infliximab 1 to 20 mg/kg, serum infliximab
`was detectable only in patients who received ..1() mg/kg. Concurrent methotrex-
`ate tended to increase serum concentrations of infliximab.
`The elimination half-life of infliximab was 9 to 10 days in patients with either
`Crohn's disease or rheumatoid arthritis. This is longer than that reported for intact
`mouse monoclonal antibodies, but shorter than that reported for native human
`antibodies.
`
`In 8- to 48-week clinical trials involving 9 to 107 patients with treatment-resistant
`Crohn's disease, infliximab 5 to 20 mg/kg achieved a clinical response [defined
`as a reduction in Crohn's disease activity index (CDAI) score of ?_70 points] in
`50 to 89% of patients. In the only fully reported, placebo-controlled trial, single
`infusions of infliximab 5, 10 or 20 mg/kg achieved a clinical response in 50 to
`81% of patients with Crohn's disease compared with 17% of patients with pla-
`cebo. Remission (defined as a CDAI score <150) was achieved in 27 to 50% of
`patients who received infliximab compared with 4% of patients who received
`placebo in this study. There was no dose-response pattern with infliximab 5, 10
`and 20 mg/kg, although the 1 mg/kg dose was associated with a lower clinical
`response rate.
`Patients with treatment-resistant Crohn's disease generally responded to a
`single infusion of infliximab by week 2, the earliest time-point reported, and
`exhibited maximum improvement by week 4 to 6. Disease activity started to
`return after approximately 8 to 12 weeks. A longer overall duration of response
`was achieved with multiple infusions of infliximab. To date, a maximum of 5
`infusions have been administered with an associated duration of effect of at least
`44 weeks.
`In patients with fistulising Crohn's disease, infliximab was significantly more
`effective than placebo on the basis of closure of fistulae. At least 50% of fistulae
`consecutive visits in 68% of patients who received in-
`were closed during (cid:9)
`fliximab 5 nig/kg compared with 26% of placebo recipients. In 55% of infliximab
`recipients, all fistulae were closed.
`
`In 4- to 26-week trials, single doses of infliximab 1 to 20 mg/kg achieved a clinical
`response in 44 to 81% of patients with rheumatoid arthritis refractory to (cid:9)
`dis-
`ease-modifying antirheumatic drug (DMARD), based on the Paulus 20% or
`American College of Rheumatology criteria (range 7 to 81 evaluable patients).
`In I trial, pain score, swollen joint count and C-reactive protein (CRP) levels were
`improved by 63, 61 and 45%, respectively, 4 weeks after patients received a single
`infusion of infliximab 10 mg/kg.
`
`Pharmacokinetic
`Properties
`
`Clinical Use in Crohn's (cid:9)
`Disease (cid:9)
`
`Clinical Potential in
`Rheumatoid Arthritis
`
`-2., Adis International Limited, All rights reserved. (cid:9)
`
`BioDrugs 1998 Nov; 10 (5)
`
`i (cid:9)
`
`: n•led
`
`Subict. (cid:9)
`
`LAYS
`
`Ex. 1090 - Page 6
`
`

`

`400
`
`Ourust & Lamb
`
`Tolerability (cid:9)
`
`Dosage and (cid:9)
`Administration (cid:9)
`
`The response to infliximab was apparent 1 week after infusion and reached a
`maximum after approximately 3 weeks. The median duration of the Paulus 20%
`response after a single infusion of infliximab 10 mg/kg was 8 weeks in 1 trial.
`Patients who were re-infused with infliximab after responding to an initial infu-
`sion and subsequently relapsing continued to respond similarly. However, the
`duration of the response was reduced with each successive infusion administered
`after relapse in a noncomparative trial in 7 patients; after 1, 2, 3 or 4 infusions,
`the median response duration was 12, 9.1, 8.3 and 7.7 weeks, respectively. Con-
`current methotrexate therapy improved the duration of the response to multiple
`infusions of infliximab.
`Adverse events associated with infliximab were usually mild and resolved spon-
`taneously. Acute, infusion-related adverse events suggestive of hypersensitivity
`(urticaria, somnolence, pruritus, chills, fever, headache, facial flushing, chest
`pain, dyspnoea and/or nausea) occurred in 6 to 38% of patients who received
`multiple infusions of inflikimab and were more common in patients with anti-in-
`fliximab antibodies. Such events were not reported in recipients of a single infu-
`sion of infliximab. The incidence of infection was slightly higher in patients who
`received infliximab than in placebo recipients. Other adverse events, at least
`possibly related to treatment, included hypertension, rigors, rash, headache and
`eczema. Two patients developed symptoms of systemic lupus erythematosus after
`multiple infusions of infliximab, and in 1 patient this was correlated with the
`development of anti-dsDNA antibodies. Five patients developed lympho-
`proliferative disorders after receiving infliximab, but the data did not establish a
`relationship between this adverse event and treatment.
`Infliximab is indicated for the management of moderate to severe, active Crohn's
`disease which does not respond to conventional therapies, and for fistulising
`Crohn's disease. The recommended dose in patients with treatment-resistant
`Crohn's disease is a single, 2-hour intravenous infusion of infliximab 5 mg/kg.
`In patients with fistulising Crohn's disease, intravenous infusions of infliximab
`5 mg/kg administered at 0, 2 and 6 weeks are recommended. Currently, no formal
`dosage recommendations are available for the administration of infliximab in
`patients with rheumatoid arthritis. In clinical trials in patients with refractory
`rheumatoid arthritis, the most effective doses of infliximab were 3 and 10 mg/kg,
`and clinical responses were maintained when infusions of infliximab were ad-
`ministered every 4 or 8 weeks.
`Because some infliximab recipients with Crohn's disease or rheumatoid ar-
`thritis have developed anti-dsDNA antibodies, hypersensitivity-type reactions or
`anti-infliximab antibodies, infliximab should be used with caution in patients
`with pre-existing anti-dsDNA antibody titres and in those who have previously
`received mouse or mouse-human monoclonal antibodies.
`
`1. Introduction
`
`Infliximab is a chimaeric monoclonal antibody
`which binds to and blocks the function of tumour
`necrosis factor-a (TNFa).[2,3] As illustrated in fig-
`ure 1, infliximab consists of 2 tc light and 271 heavy
`immunoglobulin polypeptides linked by disulph-
`
`ide bonds.ril The variable regions of the polypep-
`tides are derived from cloned cDNAs encoding the
`heavy and light chains of a mouse monoclonal an-
`tibody which has high affinity and specificity for
`human TNFa. The constant regions are derived
`from cloned cDNAs encoding human lc light and
`yi heavy polypeptides.[ I ] The resulting chimaera
`
`4::) Adis International Limited. All rights reserved.
`
`BioDrugs 1998 Nov; 10 (5)
`
`This (cid:9)
`
`•..aa :•pied
`
`La.. A.
`
`Ex. 1090 - Page 7
`
`(cid:9)
`

`

`Infliximab: A Review (cid:9)
`
`401
`
`CI Mouse
`f: Human
`— Disulphide bond
`
`Fig. 1. Diagram of infliximab, a chimaeric monoclonal antibody
`composed of mouse lc light and 71 heavy chain variable regions
`(V) and human lc light and yi heavy chain constant regions (C),
`which are joined by the disulphide bonds characteristic of immuno-
`globulins.[1]
`
`has high affinity and specificity for human TNFa,
`and blocks the function of this cytokine in vitro and
`in vivo.[ I-3 I
`Crohn's disease and rheumatoid arthritis are
`disorders with unknown aetiologies, but are prob-
`ably autoimmune in origin. They involve chronic
`inflammation of, respectively, the gastrointestinal
`tract (usually the colon and/or distal ileum) and
`multiple synovial joints.14,5I The course of both dis-
`eases is unpredictable, is usually progressive and
`may be interrupted by periods of remission.I4,5I
`Use of intravenously administered infliximab in
`the treatment of Crohn's disease and rheumatoid
`arthritis is evaluated in this review.
`
`2. Pharmacodynamic Properties
`
`Although extensive in vitro and in vivo data are
`available on infliximab, only in vivo studies of the
`effects of infliximab in patients with Crohn's dis-
`ease or rheumatoid arthritis are discussed in this
`section.
`
`2,1 Mechanism of Action
`
`Cytokines are central mediators of the localised
`inflammatory processes in both Crohn's disease
`
`and rheumatoid arthritis.[6,7] In particular, TNFa,
`the target for infliximab, is present at elevated lev-
`els in inflamed tissues and plays regulatory and
`proinflammatory roles in both diseases.[6:7I
`As outlined in figure 2, TNFa induces the ex-
`pression of chemokines, endothelial adhesion mol-
`ecules and other cytokines. As a group, these
`TNFa-induced factors promote the recruitment of
`leucocytes to inflammatory sites, leucocyte activa-
`tion and the production of acute phase pro-
`13,141
`teinsi (cid:9)
`TNFa also stimulates bone resorption
`by osteoclasts, contributing directly to bone ero-
`sion in the joints in rheumatoid arthritis,191 and the
`proliferation of fibroblasts and intestinal smooth
`muscle cells associated with intestinal fibrosis in
`Crohn's disease.112I
`Inhibition of the functions of TNFa is thought
`to be the primary mechanism of action of in-
`fliximab.I7,17I Through the complement cascade
`and/or antibody-dependent cell-mediated cytotox-
`icity, infliximab may also be cytotoxic to cells
`which express membrane-bound TNFa, such as T
`and B lymphocytes and monocytes. These cell
`types are present in the inflammatory lesions in
`Crohn's disease and rheumatoid arthritis.I3,18I
`
`2.1.1 Effects on TNFa-Regulated Factors
`As summarised in table I, infliximab decreased
`the levels of many TNFa-regulated chemokines,
`endothelial adhesion molecules and cytokines in
`biopsies of inflamed tissues and sera from patients
`with Crohn's disease or rheumatoid arthritis at
`time-points ranging from 1 day to 8 weeks after
`administration of infliximab. Biopsy examination
`is preferred because serum levels may not reflect
`short term changes in factor production at the rel-
`evant inflammatory sites.[I
`Reductions in factor levels were generally cor-
`related with clinical response to infliximab in pa-
`tients with Crohn's disease or rheumatoid arthri-
`19-21,23-25,27,28]
`tis.I (cid:9)
`Where it was administered,
`placebo had no effect on the levels of these factors
`in these patients.[20-24] A dose-response effect was
`apparent in 2 studies; the reductions in serum inter-
`cellular adhesion molecule-1 (ICAM-1), E-
`selectin and interleukin-6 (IL-6) levels in patients
`
`Adis International Limited. All rights reserved. (cid:9)
`
`BloDrugs 1998 Nov: 10 (5)
`
`Tbi,z mat i (cid:9)
`
`vied
`
`Su:S.E
`
`Ex. 1090 - Page 8
`
`

`

`402 (cid:9)
`
`Onrust & Lamb
`
`with rheumatoid arthritis were more marked with
`the 10 than the 1 mg/kg dose of infliximab.['-1,24]
`Infliximab reduced the levels of chemokines in
`biopsies from patients with Crohn's disease [mono-
`cyte chemoattractant protein-1 (MCP-1), macro-
`phage inhibitory protein-2 (MIP-2) and regulated
`upon activation, normal T cell expressed and se-
`creted (RANTES)11191 and rheumatoid arthritis (IL-
`8 and MCP-1; table 0.1261 However, the levels of
`
`growth-related peptide-a (Groa) and RANTES
`were unchanged in biopsies from patients with
`rheumatoid arthritis who received infliximab.1261
`With infliximab, endothelial adhesion molecule
`levels were reduced in biopsies from patients with
`Crohn's disease (ICAM-1)1221 and rheumatoid ar-
`thritis [E-selectin and vascular cell adhesion mol-
`ecule-1 (VCAM-1)].[201 Production of the cyto-
`kines interferon-y (IFNy) and TNFa in biopsies
`
`TNFa
`(macrophages)
`
`Endothelial
`adhesion molecules
`E-selectin
`ICAM-1
`VCAM-1
`
`(endothelial cells) (cid:9)
`
`Chemokines
`Groa MIP-2
`IL-8 RANTES
`MCP-1
`
`(macrophages,
`endothelial cells, (cid:9)
`gut epithelial cells) (cid:9)
`
`Cytokines
`IFNy
`IL-113
`IL-6
`TNFa
`
`(macrophages, T
`cells, fibroblasts)
`
`Leucocyte recruitment
`
`indicates sites of inhibitory
`; action of infliximab
`
`Leucocyte
`activation
`
`Acute phase
`proteins
`
`(hepatocytes)
`
`Bone
`resorption
`(osteoblasts)
`
`Proliferation
`(fibroblasts,
`smooth
`muscle cells)
`
`•
`Chronic inflammation
`CD: gut
`RA: synovial joints
`
`Tissue damage
`CD: fibrosis
`RA: cartilage/bone erosion
`
`Fig. 2. Proinflammatory actions of TNFa in Crohn's disease (CD) and rheumatoid arthritis (RA). TNFot induces expression of cytokines,
`chemokines and endothelial adhesion molecules. These factors function in leucocyte activation and recruitment, making major
`contributions to chronic inflammation of the intestine in CD and synovial joints in IRA. These inflammatory processes, along with
`TNFa-induced bone resorption in RA and proliferation of fibroblasts and intestinal smooth muscle cells in CD, contribute to the local
`tissue damage associated with these diseases. The cell types which are most prominently involved in the above actions of TNFa are
`shown in parentheses.i7-16I Groa = growth-related gene product-a; ICAM-1 = intercellular adhesion molecule-1; IFNy = interferon-t;
`IL = interleukin; MCP-1 = monocyte chemoattractant protein-1; MIP-2 = macrophage inflammatory protein-2; RANTES = regulated
`upon activation, normal T cell expressed and secreted; TNFa = tumour necrosis factor-a; VCAM-1 = vascular cell adhesion molecule-1.
`
`Adis International Limited. All rights reserved. (cid:9)
`
`BioDrugs 1998 Nov; 10 (5)
`
`owied
`Thi: s:e•ia I (cid:9)
`a.rad nia,be
`
`Ex. 1090 - Page 9
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`

`

`Infliximab: A Review (cid:9)
`
`403
`
`Table I. Effects of infliximab (INF) on the levels of TNFcx-induced factors in biopsies of inflamed tissues or sera taken from patients with
`Crohn's disease (CD) or rheumatoid arthritis (RA). In each study, patients received a single infusion of INF 1, 5, 10 or 20 mg/kg (dose was
`not specified in 2 studies).[17.191 Some studies were placebo-controlled; placebo did not reduce factor levels.12°-241 Most studies included X15
`patients, but 2 were larger and included 68121] and 1081231 patients, respectively. Five of the 9 studies referred to below were published as
`abstracts[19,22,23,25.261
`
`Factor (cid:9)
`
`Disease Effect of INF on
`factor levela
`biopsy (cid:9)
`serum
`
`Correlation
`with clinical
`response
`
`Comments
`
`Reference
`
`Chemokines
`Groa
`RA
`IL-8
`RA
`MCP-1
`CD
`RA
`MIP-2
`CD
`RANTES CD
`RA
`
`<-> vs bit
`11 vs bl
`.I. vs bl
`11 vs bl
`,I. vs bl
`1 vs bl
`<-> vs bit
`
`NR
`NR
`Yes
`NR
`Yes
`Yes
`NR
`
`Evaluation was at week 2
`
`Levels were reduced 64% from baseline at week 2
`Evaluation was at week 4
`
`Levels were reduced 45% from baseline at week 2
`Evaluation was at week 4
`Evaluation was at week 4
`Evaluation was at week 2
`
`Endothelial adhesion molecules
`E-selectin RA
`.11 vs bl (cid:9)
`11 vs PL Yes
`
`ICAM-1
`
`CD
`
`,l, vs PL (cid:9)
`
`11 vs PL Yes
`
`RA
`
`14 vs PL Yes
`
`VCAM-1 RA
`
`11 vs bl (cid:9)
`
`<-> vs PL Yesb
`
`CD
`
`1 vs bl
`
`Yes
`
`Cytokines
`IFNy (cid:9)
`
`IL-10
`
`IL-6
`
`RA
`
`CD
`CD
`
`RA
`
`11 vs PL Yes
`
`<-> vs PL No
`1 vs bl
`Yes
`
`11 vs PL
`or bl
`
`Yes
`
`Yes
`
`TNFU
`
`CD
`
`1 vs bl
`
`RA
`
`T vs bl
`
`NR
`
`Levels in biopsies were reduced 60% from baseline at week
`4.120] In sera, levels were reduced -30% from baseline with INF
`10 mg/kg and -8% with INF 1 mg/kg at weeks 2 and 4[211
`Biopsies were evaluated at week 4.122] In sera, levels were
`reduced -5 to 10% from baseline at weeks 2 and 41231
`Levels were reduced 25 or 35% from baseline with INF 10
`mg/kg and 16 or 6% with INF 1 mg/kg at weeks 2 or 4,
`respectively1211
`In biopsies, levels were reduced 36% from baseline at week
`4.1201 Sera were evaluated at weeks 2 and 4121)
`
`At weeks 4 and 8, <0.1% of biopsy-derived mononuclear cells
`produced IFNy compared with 2.2% at baseline
`
`Levels were reduced -50 to 70% from baseline with either INF 1
`or 10 mg/kg on days 1 and 7
`
`Evaluations were at weeks 2 and 4
`Levels were reduced -50% from baseline at weeks 2, 4 and 6,
`and -30% at week 8
`Levels were reduced -75 to 90% from baseline with INF 1 or 10
`mg/kg on days 1 and 71241
`At weeks 4 or 8, 2 to 3% of biopsy-derived mononuclear cells
`produced TNFa compared with 5% at baseline
`Levels of -100 ng/L were detected by ELISA but not by bioassy
`24 hours after patients received INF. At baseline, TNFa was
`typically undetectable by ELISA or bioassay
`
`26
`26
`19
`26
`19
`19
`26
`
`20,21
`
`22,23
`
`21,24
`
`20,21
`
`27
`
`24
`
`23
`25
`
`24,28
`
`27
`
`17
`
`a (cid:9) Biopsies were assayed by immunohistochemistry[19,20,22,261 or in vitro culture of biopsy-derived mononuclear cells with subsequent
`measurement of factor levels in culture medium by specific ELISAs.1271 Sera were assayed by factor-specific ELISAs[21,23,25,28] or an
`unstated method.1241
`b (cid:9) Based on results in biopsy specimens.
`
`bl = baseline; ELISA = enzyme-linked immunosorbent assay; Groa = growth-related gene product-a; ICAM-1 = intercellular adhesion
`molecule-1; IFNy = interferon-y, IL = interleukin; MCP-1 = monocyte chemoattractant protein-1; MIP-2 = macrophage inflammatory protein-2;
`NR = not reported; PL = placebo; RANTES = regulated upon activation, normal T cell expressed and secreted; TNFc = tumour necrosis
`factor-a; VCAM-1 = vascular cell adhesion molecule-1; 11 indicates significantly reduced level (p < 0.05); 1 indicates reduced level, no
`statistics reported; T indicates increased level, no statistices reported; <-> indicates no change in level; indicates no statistics were reported.
`
`Adis International Limited. All rights reserved. (cid:9)
`
`BloDrugs 1998 Nov: 10 (5)
`
`This matsrial. 3i
`at the NC.f E` rr :3
`Subject US Cap ,ri=ot Laws
`
`Ex. 1090 - Page 10
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`

`

`404
`
`Onrust & Lamb
`
`was also reduced by infliximab in 1 study:1271 when
`mononuclear cells isolated from biopsies obtained
`from 4 patients with Crohn's disease who had re-
`sponded to infliximab were cultured in vitro, these
`cells produced markedly reduced levels of IFNy
`and TNFa when compared with baseline. Such a
`reduction in IFNy and TNFa production was not
`observed in 1 patient who received infliximab but
`did not achieve a clinical response.1271
`The effects of infliximab on the levels of e