New Drug Class
`
`Lancet 2008; 372: 67–81
`Hôpital Claude Huriez, Centre
`Hospitalier Universitaire de
`Lille, Lille, France
`(L Peyrin-Biroulet MD,
`Prof P Desreumaux MD,
`Prof J-F Colombel MD); and
`Mayo Clinic, Rochester, MN,
`USA (Prof W J Sandborn MD)
`Correspondence to:
`Prof Jean-Frédéric Colombel,
`Hôpital Claude Huriez, Centre
`Hospitalier Universitaire de Lille,
`Rue Michel Polonovski, Lille
`59037, France
`jfcolombel@chru-lille.fr
`
`Crohn’s disease: beyond antagonists of tumour necrosis
`factor
`
`Laurent Peyrin-Biroulet, Pierre Desreumaux, William J Sandborn, Jean-Frédéric Colombel
`
`In the past few years, antagonists of tumour necrosis factor have resulted in unforetold therapeutic benefi ts in Crohn’s
`disease, but the magnitude and duration of responses are variable. New agents are therefore needed. Their
`development has benefi ted from advances in the understanding of the pathophysiology of this disease. Uncontrolled
`activation of the acquired immune system has an important role, and lymphocytes, cytokines, and adhesion molecules
`are broadly targeted for therapeutic intervention. With increasing evidence of an implication of the innate immune
`system and the intestinal epithelium, the therapeutic paradigm is also shifting from mere immunosuppression to the
`reinforcement of the intestinal barrier. We review mechanisms of actions of new drugs and the effi cacy and adverse
`events from data from clinical trials. We discuss future directions, including new strategies with optimum
`endpoints.
`
`Introduction
`Crohn’s disease results from a dysregulated response of
`the mucosal immmune system to intraluminal antigens
`of bacterial origin
`in people who are genetically
`predisposed to this disease.1,2 The traditional view of the
`pathogenesis of Crohn’s disease is that intestinal
`infl ammation is mediated by cells of the acquired
`immune system, with overly aggressive activity of eff ector
`lymphocytes and proinfl ammatory cytokines.1,2 Emerging
`evidence suggests that disease development implicates a
`dysregulated dialogue between the intestinal microbiota
`and components of both the innate and adaptive immune
`systems.3,4 The host response to the intestinal microbiota
`can be categorised into three basic components: the
`intestinal epithelium, innate immune cells of the myeloid
`lineages (eg, monocytes, dendritic cells, and granulocytes),
`and adaptive immune cells (B and T cells) (fi gure 1).
`Models with defects in each of these components have
`been associated with pathogenesis of infl ammatory
`bowel disease in mice.3,4
`identify a
`to
`long sought
`Investigators have
`micro-organism that causes infl ammatory bowel disease.
`The present theory suggests a breakdown in the balance
`between putative species of protective versus harmful
`bacteria—a notion that has been termed dysbiosis.5
`Recent studies emphasised the potential importance of
`adherent invasive Escherichia coli in the initiation and
`maintenance of infl ammation in Crohn’s disease.6,7
`However, our understanding of the microbial fl ora is still
`incomplete. Metagenomic and computational analyses of
`the so-called microbiome might provide a foundation to
`achieve a more accurate understanding of the relevant,
`functional diversity of the fl ora in the context of
`infl ammatory bowel disease.4,8
`The intestinal epithelium, which is considered to be
`part of the innate immune system, has an active role in
`maintenance of mucosal homoeostasis. Epithelial cells
`form a tight, highly selective barrier between the body
`and the intraluminal environment. Failure of this barrier
`can result in intestinal infl ammation, most likely through
`exposure to fecal antigens leading to inapppropriate
`
`activation of the mucosal immune system.1 In human
`beings, the importance of the epithelial barrier in disease
`predisposition is supported by the fi nding of abnormal
`intestinal permeability in fi rst-degree relatives of patients
`with Crohn’s disease.4,9
`The innate immune system is the body’s non-specifi c
`defence against pathogens. It is regarded as the fi rst line
`of defence that reacts to the chemical properties of the
`antigen.1 Evidence of the role of the innate immune
`system comes from the identifi cation of nucleotide-binding
`oligomerisation domain containing 2
`(NOD2) as a
`susceptibility gene for Crohn’s disease.10,11 Individuals
`who are either homozygotes or compound heterozygotes
`for any one of the three germline variations of NOD2
`that are commonly identifi ed have as much as a 40-fold
`increased likelihood of developing ileal Crohn’s disease.
`The NOD2 protein is an intracellular receptor for a
`component of the bacterial cell wall, and is expressed in
`macrophages, dendritic cells, intestinal epithelial cells,
`and Paneth cells, providing specifi c support for the
`long-held hypothesis that Crohn’s disease results from a
`genetically dysregulated host immune response to
`luminal bacteria.4 Furthermore, natural antimicrobial
`peptides, such as defensins, are expressed in an
`NOD2-dependent manner, and patients with this disease
`
`Search strategy and selection criteria
`
`We did a computerised search of English and non-English
`language publications listed in the electronic databases of
`Medline (source PubMed, from 1966 to March, 2008), the
`Cochrane Library, and Embase (from 1980 to March, 2008).
`We searched for the terms: “Crohn’s disease”, “infl ammatory
`bowel disease”, “treatment”, “biological therapy”,
`“cytokine”, “T-cell”, “adhesion”, “growth factors”. We also
`hand-searched abstracts from the yearly meetings of
`Digestive Disease Week between 2003 and 2007, and the
`United European Gastroenterology Week between 2003
`and 2007, and references from review articles and published
`trials to identify additional articles.
`
`www.thelancet.com Vol 372 July 5, 2008
`
`67
`
`MYLAN - EXHIBIT 1028
`
`

`

`New Drug Class
`
`See Online for webfi gure 1
`
`can have reduced defensin production in their intestine,12
`contributing to inadequate microbial clearance.
`Adaptive immunity is the most proximate driver of
`tissue damage that arises in patients with infl ammatory
`bowel disease, although innate immune responses seem
`to be a prerequisite for the excessive activation of adaptive
`immunity.4 Adaptive responses toward a specifi c antigen
`are aff ected by a combination of resident and recruited
`cell populations. These populations consist of mucosal
`B cells producing immunoglobulins and a mixture of
`T cells that are dominated by a T-helper (Th) 1, Th2, or
`Th17 phenotype, and
`the coincident presence of
`regulatory T or B cells.4 Th1 development is triggered by
`microbes that stimulate production of interleukin-12p40
`and interferon γ, which then activate macrophages and
`the release of interleukin 1, interleukin 6, and tumor
`necrosis factor α (TNFα) (fi gure 1 and webfi gure 1).
`Classic Crohn’s disease has a Th1-type cytokine profi le.
`Another CD4 T-cell lineage (Th17) that is distinct from
`Th1 and Th2 has now been linked to the pathogenesis of
`Crohn’s disease. In a genome-wide association study
`involving a North American case-control cohort with this
`
`disease, typing more than 300 000 single nucleotide
`polymorphims, an interleukin 23R coding variant was
`associated with reduced risk of infl ammatory bowel
`disease.13 Th17-cell development is driven by transforming
`growth factor β (TGFβ) and interleukin 6, whereas
`interleukin 23 seems to expand and maintain Th17-cell
`populations. The interleukin-23 receptor consists of the
`interleukin-23R subunit and interleukin 12RB1, whereas
`the interleukin-23 cytokine consists of p19 and p40
`subunits.3 In addition to helper-cell activation, evidence
`in human beings and murine models also suggest a role
`for regulatory T cells producing interleukin 10 or TGFβ,
`or both, in maintenance of intestinal homoeostasis4
`(webfi gure 1).
`Over the past decade, the advent of antiTNFα agent
`infl iximab has changed the way that refractory Crohn’s
`disease is treated. Infl iximab rapidly induces and
`maintains response and remission,14,15 spares steroids,15,16
`and
`induces
`and maintains fi stula
`closure.17,18
`Nevertheless, about a third of patients do not respond at
`all to this drug, and an additional third has only some
`response. This fi nding can be explained by the presence
`
`Luminal antigens (bacteria)
`
`D
`Teduglutide (GLP-2)
`Somatropin (GH)
`
`TNFα
`
`IL-12
`
`IL-1
`
`IL-8
`
`IL-6
`
`Macrophage activation
`
`A
`ABT-874
`Ustekinumab
`Toclizumab
`Apilimod
`
`Natalizumab
`MLN-0002
`Alicaforsen
`CCX282-B
`
`PMN
`
`ICAM-1
`
`C
`
`Leucocyte migration and activation
`
`Th2
`
`Th1
`
`Th17
`
`CD4+, T-cell activation
`
`A
`Fontolizumab
`ABT-874
`Ustekinumab
`
`B
`Visilizumab
`Daclizumab
`Basiliximab
`Abatacept
`
`D
`Sargramostim (GM-CSF)
`Filgrastim (G-CSF)
`Somatropin (GH)
`
`Figure 1: Overview of therapeutic targets in Crohn’s disease: cytokine therapies (A), T-cell blocking agents (B), antiadhesion molecules (C), and
`growth factors (D)
`The host response to the intestinal microbiota can be categorised into three basic components: the intestinal epithelium, innate immune cells of the myeloid lineages
`(including macrophages and granulocytes), and adaptive immune cells (including CD4+ T-helper 1 cells). The most crucial environmental factor in the pathogenesis
`of Crohn’s disease might be the luminal fl ora. Defects in the intestinal innate immune barrier (consisting of several cell types including the epithelial and immune
`cells), leading to aberrant early innate immune response towards bacterial threats, might start an excessive adaptive immune response dominated by mucosal CD4+
`lymphocytes. Classic Crohn’s disease has a predominant Th1 cytokine profi le that is characterised by interleukin 12 and interferon γ. TNF=tumour necrosis factor α.
`ICAM-1=intercellular adhesion molecule-1. GM-CSF=granulocyte-macrophage colony-stimulating factor. G-CSF=granulocyte colony-stimulating factor. GH=growth
`hormone. Th=T-helper. GLP-2=glucagon-like peptide 2. IL=interleukin. PMN=polymorphonuclear.
`
`68
`
`www.thelancet.com Vol 372 July 5, 2008
`
`

`

`New Drug Class
`
`in responders and
`of diff erent eff ector pathways
`non-responders.1 Newer antiTNF drugs such as
`certolizumab pegol and adalimumab have similar effi cacy
`to infl iximab.19–21 Patients who have been previously given
`infl iximab who have lost response or become intolerant
`can respond to alternative biological drugs targeting
`TNF.22 However, an overall decrease is noted in the
`absolute proportion of responses to the second agent,
`suggesting that some patients who previously responded
`might not have benefi ts of targeting TNF.22 This fi nding
`emphasises the need for developing novel biological
`drugs for the treatment of Crohn’s disease.
`These advances in our understanding of the patho-
`physiology of infl ammatory bowel disease have led to
`new
`therapeutic
`opportunities
`(fi gures
`1
`and
`webfi gure 1).2,23 The many therapies being investigated
`include cytokine and anticytokine therapies, T-cell
`blocking agents, anti adhesion molecules, and new
`immuno modulatory strategies (tables 1 and 2). In this
`review, we will discuss mechanisms of action of new bio-
`logical drugs, their effi cacy, and safety profi les, and will
`review previous innovative therapies and future direc-
`tions for treatment of Crohn’s disease (table 3).
`
`Mechanisms of action of novel biological therapies
`T-cell blockade
`The T cell is pivotal in orchestration and promotion of the
`immune response in infl ammatory bowel disease. Most
`therapies for infl ammatory bowel disease aim to inhibit
`T-cell
`function, block
`the generation of T-cell
`pro-infl ammatory cytokines, or induce apoptosis of T cells
`or a particular subset of these cells.23 CD4+ T lymphocytes
`recognise antigens that have been processed and are
`presented in association with a self class II MHC molecule
`to initiate the immune response.23,74 After the development
`of CD4+ T-cell antagonists, such as cM-T412,24,25 other
`antibodies have been generated against more specifi c
`T-cell subsets: CD3+ cells (visilizumab) and CD25+
`(daclizumab and basiliximab).23 Visilizumab is a non-Fc
`receptor-binding antiCD3 monoclonal antibody directed
`against the invariant CD3ε chain of the T-cell receptor
`(webfi gure 2).75 Unlike the prototypic murine antiCD3
`monoclonal antibodies, which induce T-cell activation by
`FcR binding and recruitment of antigen-presenting cells,
`non-FcR-binding antiCD3 monoclonal antibodies do not
`activate resting T cells and therefore induce less toxic
`eff ects from cytokine release in vivo.75
`Visilizumab induces apoptosis selectively in activated
`T cells, and it is much more eff ective in this respect than
`are murine
`antiCD3 monoclonal
`antibodies
`(webfi gure 2). Two antibodies against the interleukin-2
`receptor (CD25)—namely, daclizumab and basiliximab,
`have been studied to mimic the activity of cyclosporine,
`which acts by disruption of the calcineurin pathway.
`Additionally, because interleukin 2 induces steroid
`resistance, blockade of this receptor should in principle
`abrogate this eff ect.23
`
`Blockade of T-cell diff erentiation or activation
`Instead of depletion of a particular T-cell subset, another
`approach has been to block steps in T-cell development
`by targeting cytokines and molecules that are involved
`in T-cell diff erentiation and activation (webfi gure 1).23
`Interleukin 6 is a pleiotropic cytokine that is released in
`response to interleukin 1 and TNFα, with central roles
`in immune regulation and infl ammation.76 Accordingly,
`interleukin 6 off ers an attractive target to interrupt
`infl ammation in infl ammatory bowel disease at several
`points. Increased serum concentrations of soluble inter-
`leukin 6R were detected in the active stage of infl am-
`matory bowel disease.77 Tocilizumab (formerly atlizumab)
`binds to both the membrane-bound form and the
`soluble form of human interleukin 6R with high affi nity
`and specifi city.28 Fontolizumab is a humanised anti body
`directed against interferon γ, which is a key Th1 cyto-
`kine driving expression of MHC class II on antigen
`presenting cells, increasing chemokine secretion and
`activating macrophages, lymphocytes, and endothelial
`cells.76 Because of the proinfl ammatory role of inter-
`leukin 23,3 attention is now being focused on molecules
`specifi cally targeting the interleukin-23 p19 subunit in
`addition
`to developing drugs—such as apilimod
`mesylate (STA 5326), ABT-874, and ustekinumab
`(CNTO 1275)—which block both interelukin-23 and
`interleukin-12 activities.32,34,78
`T cells need both antigen-specifi c and costimulatory
`signals for their full activation (fi gure 2).79 ch5D12 blocks
`the CD40/CD40L costimulatory pathway; CD40 belongs
`to the TNF receptor family.79 On the basis of a second
`T-cell surface molecule that is homologous to CD28—
`CTLA-4 (CD152), which has a 20-fold higher affi nity for
`the CD80 and CD86 ligands than does CD28—abatacept
`has been developed (fi gure 2).79 Another selective
`costimulation blocker, belatacept (LEA29Y), was designed
`by substitution of two amino acids in the abatacept
`CD80/CD86-binding domain to increase avidity to CD86
`and provide the potency needed for immunosuppression
`in transplantation.79 It has not yet been tested in
`infl ammatory bowel disease.
`
`Resetting T-cells
`Patients with Crohn’s disease receiving allogeneic bone-
`marrow tansplants for unrelated disorders had extended
`remission of their Crohn’s disease, providing evidence of
`the role of bone-marrow T cells (either T-helper or
`regulatory T cells) in this disease.80 Although not curative,
`reconstitution of a normal T-cell balance by autologous
`haemopoietic stem-cell transplantation resulting in the
`elimination of all circulating T cells has been used to
`treat a range of autoimmune, T-cell driven diseases,23
`including multiple sclerosis and rheumatoid arthritis.81
`In theory, a transplant conditioning regimen would
`ablate aberrant disease-causing immune cells, whereas
`haemopoietic
`stem
`cells would
`regenerate
`an
`antigen-naive immune system.
`
`See Online for webfi gure 2
`
`www.thelancet.com Vol 372 July 5, 2008
`
`69
`
`

`

`New Drug Class
`
`Development
`status
`
`Compound
`
`Manufacturer
`
`Target
`
`Compound class
`
`Clinical effi cacy
`
`Biological
`effi cacy (CRP)
`
`References
`
`T-cell blockade
`
`Phase I/II
`
`cM-T412
`
`Visilizumab
`
`Blockade of T-cell
`diff erentiation or
`activation
`
`Phase III
`
`Abatacept*
`
`Phase I/II
`
`Tocilizumab
`
`Centocor, Malvern, PA,
`USA
`PDL Biopharma,
`Fremont, CA, USA
`
`Bristol Mayers Squibb,
`New York, NY, USA
`
`CD4 on T-cell surface Chimeric mAb
`
`CD3 on T-cell surface Humanised Fc IgG2
`receptor -non-binding
`mAb
`Soluble recombinant
`fusion protein
`
`Blockade of CD28
`costimulatory
`pathway
`IL-6 receptor
`
`Humanised mAb
`
`Fontolizumab/
`HuZAF
`ABT-874/ J695
`
`Ustekinumab
`(CNTO 1275)
`Apilimod mesylate/
`STA 5326
`ch5D12
`
`Interferon γ
`
`Humanised mAb
`
`IL-12/IL-23, p40
`
`Humanised mAb
`
`IL-12/IL-23, p40
`
`Human mAb
`
`IL-12/23
`
`Small molecule
`
`Chimeric mAb
`
`Cell therapy
`
`Resetting T cells
`
`Phase I/II
`
`Induction Maintenance
`
`No placebo
`group
`No placebo
`group
`
`NA
`
`NA
`
`NA
`
`+
`
`Not yet
`available
`
`Not yet
`available
`
`Not yet
`available
`
`+
`
`–
`
`+
`
`+
`
`No control
`group
`No placebo
`group
`No placebo
`group
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`+
`
`+
`
`NA
`
`+
`
`NA
`
`NA
`
`NA
`
`+
`
`24,25
`
`26,27
`
`NA
`
`28
`
`29–31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`37,38
`
`Chugai Pharmaceuticals,
`Fremont, CA, USA
`PDL Biopharma,
`Fremont, CA, USA
`Abbott, Parsipanny, PA,
`USA
`Centocor, Malvern, PA,
`USA
`Synta Pharmaceuticals,
`Lexington, MA, USA
`Tanox, Houston, TX, USA CD40 on antigen-
`presenting cells
`Autologous
`haemopoietic stem
`cells
`JNK and p38 MAP
`kinases
`
`Northwestern University,
`Evanston/Chicago, IL,
`USA
`Cytokine PharmaSciences
`Inc, King of Prussia, PA,
`USA
`Boehringer Ingelheim
`Pharmaceuticals,
`Ridgefi eld, CT, USA
`
`p38 MAP kinase
`
`AntiTNF
`strategies
`
`Phase I/II
`
`Haemapoietic stem
`cell
`transplantation†
`Semapimod/CNI-
`1493
`
`Doramapimod/
`BIRB 796
`
`Thalidomide
`
`Pharmion, Camberley,
`UK
`
`Antiangiogenic and
`anti-infl ammatory
`(TNFα) properties
`IL-10
`
`Shering-Plough,
`Kenilworth, NJ, USA
`Wyeth, Madison, NJ, USA IL-11
`
`ActoGeniX, Ghent,
`Belgium
`
`IL-10
`
`Regulatory T-cell
`modulation
`
`Phase I/II
`
`IL-10
`
`Oprelvekin/IL-11
`
`Lactococcus lactis
`(LL-Thy12)
`expressing mature
`human IL-10
`Natalizumab
`
`Blocking cell
`recruitment
`
`Phase III
`
`Elan, Dublin, Ireland
`
`Leucocyte α4β1 and
`α4β7 integrins
`Endothelial ICAM-1
`
`Alicaforsen/ISIS-
`2302
`
`Isis Pharmaceuticals,
`Carlsbad, CA, USA
`
`Phase II
`
`CCX282-B
`
`MLN-0002/
`LDP-02‡
`
`ChemoCentryx,
`Mountain View, CA, USA
`Millennium
`Pharmaceuticals,
`Cambridge, MA, USA
`
`Antichemokine
`receptor CCR9
`Leucocyte α4β7
`integrin
`
`Synthetic
`guanylhydrazone
`
`No placebo
`group
`
`NA
`
`Small molecule
`(member of the N-
`pyrazole-N-naphthly
`urea class)
`Synthetic derivative of
`glutamic acid
`
`Recombinant human
`cytokine
`Recombinant human
`cytokine
`Living non-pathogenic
`micro-organisms
`expressing IL-10
`(TopAct system)
`Humanised mAb
`
`Phosphorothioate-
`modifi ed antisense
`oligodesoxynucleotide
`Small molecule
`
`Humanised mAb
`
`–
`
`NA
`
`+
`
`No placebo
`group
`
`No placebo
`group
`
`–
`
`–
`
`NA
`
`NA
`
`No placebo
`group
`
`No placebo
`group
`
`+
`
`–
`
`+/–
`
`+/–
`
`+
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`–
`
`NA
`
`+
`
`NA
`
`+/–
`
`–
`
`39
`
`40
`
`41–43
`
`44–46
`
`47
`
`48–56
`
`57–62
`
`63,64
`
`65
`
`(Continues on next page)
`
`AntiTNF strategies
`In addition to TNF antagonists—such as infl iximab,
`adalimumab,
`and
`certolizumab—other
`antiTNF
`approaches have been developed to treat infl ammatory
`bowel disease. Mitogen-activated protein
`(MAP)
`kinases, belonging to the family of serine or threonine
`
`kinases, constitute major NF-kB-independent infl am-
`matory signalling pathways from the cell surface to the
`nucleus. Four major groups of distinctly regulated
`groups of MAP kinase cascades led to altered gene
`expression: ERK1/2, ERK5, JNK, and p38 MAP kinase.
`Because only p38 MAP kinase and JNK pathways
`
`70
`
`www.thelancet.com Vol 372 July 5, 2008
`
`

`

`New Drug Class
`
`Development
`status
`
`Compound
`
`Manufacturer
`
`Target
`
`Compound class
`
`Clinical effi cacy
`
`Biological
`effi cacy (CRP)
`
`References
`
`(Continued from previous page)
`Enhancing repair
`Phase II
`
`Teduglutide/ALX-
`0600
`Somatropin/
`
`Innate immune
`stimulation
`
`Phase III
`
`Sargramostim
`
`Phase I/II
`
`Filgrastim
`
`Induction of oral
`tolerance
`
`Phase I/II
`
`Aleqel
`
`Opebacan
`
`NPS Pharmaceuticals, Salt
`Lake City, UT, USA
`Eli Lilly,Indianapolis, IN,
`USA
`Berlex (Schering AG),
`Berlin, Germany
`
`Amgen, Thousand Oaks,
`CA, USA
`Enzo Therapeutics,
`Farmingdale, NY, USA
`Xoma, Berkeley, CA, USA
`
`Analogue of human
`Intestinal GLP-2
`peptide GLP-2
`receptors
`Intestinal epithelium GH peptide
`
`Intestinal epithelium,
`neutrophils,
`monocytes
`Neutrophils
`
`Induction of oral
`tolerance
`Induction of oral
`tolerance
`
`Yeast-derived
`recombinant human
`GM-CSF
`E coli-derived human
`(G-CSF)
`Autologous colonic
`extracts
`Autologous colon-
`derived antigens
`
`Induction
`
`Maintenance
`
`+
`
`+
`
`+/–
`
`NA
`
`NA
`
`NA
`
`No placebo
`group
`–
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`NA
`
`–
`
`Not yet
`available
`
`Not yet
`available
`
`Not yet
`available
`
`66
`
`67
`
`68–71
`
`72
`
`73
`
`NA
`
`NA=not available. IL=interleukin. TNF=tumour necrosis factor. ICAM-1= intercellular adhesion molecule-1. GLP-2=glucagon-like peptide-2. mAb=monoclonal antibody. MAP=mitogen-activated protein.
`GH=growth hormone. GM-CSF=granulocyte-macrophage colony-stimulating factor. GCSF=granulocyte colony-stimulating factor. CRP=C-reactive protein. *Phase III trials are in progress in Crohn’s disease
`(abatacept has been approved by the US Food and Drug Administration for rheumatoid arthritis). †Phase II trials are in progress in Crohn’s disease (results presented here come from phase I trials). ‡Phase III trials
`are anticipated in Crohn’s disease (results presented here come from phase II trials).
`
`Table 1: Effi cacy of biological agents in clinical trials in Crohn’s disease
`
`to pro-infl ammatory response, specifi c
`contribute
`inhibitors, including semapimod and doramapimod
`(BIRB 796)37–39 were tested in infl ammatory bowel
`disease. Several therapies, which are presented as
`TNFα inhibitors, have a more general immunomodu-
`latory eff ect and are fairly weak inhibitors—such as
`thalidomide.40 RDP58 is a decapeptide that is orally
`available and reduces the activity of TNFα, interleukin 2,
`interleukin 12, and interferon γ.23,82
`
`Regulatory T-cell modulation
`Regulatory T cells function to control the infl ammatory
`process directed by other T-helper cells. Interleukin 10 is
`one of the prototypic products of regulatory T cells and
`downregulates activation of Th-cell subsets. Interleukin 10
`also
`inhibits macrophage
`infl ammatory
`cytokine
`production including TNFα, interleukins 1 and 12, and
`T-cell associated macrophage activity. Interleukin 10 has
`therapeutic eff ects in several preclinical murine models
`of colitis.23
`
`Blocking cell recruitment
`Most of the strategies detailed above aim to interrupt
`cytokine activity through the inhibition of pathways
`promoting cytokine production, or by directly blocking
`cytokine action. A diff erent approach aims to block
`leucocyte migration
`to sites of
`infl ammation by
`interfering with
`cell-adhesion molecules.23 Most
`leucocytes,
`including
`lymphocytes, monocytes,
`eosinophils, and basophils, express α4 integrin adhesion
`molecules.83,84 The integrins are a large family of
`heterodimeric, transmembrane glycoproteins that are
`capable of mediating both cell–cell and cell–matrix
`interactions.85 Subunits of α4 integrin are most frequently
`
`found adjoined with β1 and β7 subunits. Endothelial
`ligands for α4 integrins include members of the
`immunoglobulin superfamily of adhesion molecules,
`vascular cell adhesion molecule-1 (VCAM-1), and mucosal
`addressin cell adhesion molecule-1
`(MAdCAM-1)
`(fi gure 3).83,84 Inhibitors of selective adhesion molecules
`interfering with the migration of leucocytes from the
`bloodstream to the sites of infl ammation—a process
`known as diapedesis—have been developed. Natalizumab
`and MLN-0002 bind specifi cally to α4 integrins, whereas
`the anti-intercellular adhesion molecule-1 (ICAM-1) anti-
`sense oligonucleotide ISIS-2302 (alicaforsen) blocks the
`endothelial cell adhesion molecules (fi gure 3). ICAM-1
`binds β2-integrin leucocyte function-associated antigen-1
`(LFA-1). CCX282-B is a drug that targets the chemokine
`receptor 9 (CCR9), which is a highly specifi c receptor
`expressed by T cells migrating selectively to the digestive
`tract. CCR9-positive cells are recruited into the epithelium
`of the small intestine because they respond specifi cally to
`the CCR9 ligand CCL25 (also called TECK [thymus-
`expressed chemokine]) expressed by small-intestine cells,
`and to a lesser extent by colonic cells.85 Another means to
`prevent cells from migrating to sites of infl ammation
`uses extracorporeal devices (for instance Adacolumn,
`Otsuka, Tokyo, Japan) to fi lter out or lyse leucocytes
`subsets from whole blood.86
`
`Enhancing repair
`Rather than interfering with infl ammation, teduglutide,
`a dipeptidyl peptidase IV resistant glucagon-like
`peptide-2 (GLP-2) analogue,66 and somatropin, a growth
`hormone, can overcome the detrimental eff ects of the
`infl ammatory process by driving restitution of the
`epithelium.67 GLP-2 is a 33 aminoacid peptide, which is
`
`www.thelancet.com Vol 372 July 5, 2008
`
`71
`
`

`

`New Drug Class
`
`secreted from entero endocrine L cells in the distal ileum
`and colon in a biphasic pattern, in response to nutrient
`ingestion including glucose, fatty acids, and dietary
`fi bre; it stimulates intestinal growth through poorly
`
`understood paracrine or neural pathways, or both.87
`Action of growth hormone is mostly mediated by
`growth-hormone-dependent hepatic prod uction of
`insulin-like growth factor-1, which has been defi ned as
`
`Compound
`
`Half-life
`
`Mode of
`administration
`
`Adverse eff ects
`
`References
`
`Immunogenicity
`(% antibodies
`against compound
`in the active group)
`
`T-cell blockade
`
`Blockade of T-cell
`diff erentiation or
`activation
`
`cM-T412
`Visilizumab
`
`Abatacept*
`
`NA
`NA
`
`Intravenous
`Intravenous
`
`13 days
`
`Intravenous
`
`Fever, chills, headhache; sigmoid perforation (one case)
`Transient increase of transaminases, headache, pyrexia, cytokine
`release syndrome
`Headache, nasopharyngitis, dizziness, infusion reactions*
`
`NA
`NA
`
`1·4%*
`
`Not applicable
`
`47
`
`8–9·5%
`
`48–56
`
`Filgrastim
`Aleqel
`
`Opebacan
`
`Subcutaneous
`3·5 h
`Not applicable Not applicable
`
`Bone pain, viral-like syndrome (one case)
`No treatment-related adverse events
`
`Not applicable Not applicable
`
`Not yet available
`
`NA
`Not applicable
`
`Not applicable
`
`NA=not available. TNF=tumour necrosis factor. IL=interleukin. *Data from trials in rheumatoid arthritis. †Data from trials in ulcerative colitis.
`
`Table 2: Adverse eff ects of biological agents (with their method of administration, half-life, and immunogenicity) in clinical trials in Crohn’s disease
`
`72
`
`www.thelancet.com Vol 372 July 5, 2008
`
`Tocilizumab
`
`4 days
`
`Intravenous
`
`Fontolizumab/HuZAF
`ABT-874/J695
`Ustekinumab (CNTO 1275)
`
`Apilimod mesylate/STA 5326
`ch5D12
`Haemapoietic stem-cell
`transplantation
`Semapimod/CNI-1493
`Doramapimod/BIRB 796
`Thalidomide
`IL-10
`
`Oprelvekin/IL-11
`
`18 days
`NA
`NA
`
`Intravenous
`Subcutaneous
`Intravenous,
`subcutaneous
`Oral
`NA
`Intravenous
`8–10 days
`Not applicable Not applicable
`
`NA
`NA
`5–8 h
`1·5–3 h
`
`2–3 h
`
`Intravenous
`Oral
`Oral
`Subcutaneous
`
`Subcutaneous
`
`Lactococcus lactis (LL-Thy12)
`expressing mature human IL-10
`Natalizumab
`
`Not applicable Oral
`
`132–161 h
`
`Intravenous
`
`Resetting T-cells
`
`AntiTNF strategies
`
`Regulatory T-cell
`modulation
`
`Blocking cell
`recruitment
`
`Alicaforsen/ISIS-2302
`
`1·5 h
`
`CCX282-B
`MLN-0002/LDP-02
`Teduglutide/ALX-0600
`
`Enhancing repair
`
`Somatropin
`
`NA
`9–12 days
`7 min (for
`intravenous
`formulation)
`3 h
`
`Intravenous (or
`subcutaneous in
`one study)
`Oral
`Intravenous
`Subcutaneous
`
`Subcutaneous
`
`Sargramostim
`
`NA
`
`Subcutaneous
`
`Innate immune
`stimulation
`
`Induction of oral
`tolerance
`
`Common cold, nausea, pharyngolaryngeal pain, headache,
`retching, vomiting, insomnia; gastrointestinal bleeding
`(two cases), paralytic ileus (one case)
`Asthenia, chills, fever
`Injection-site reactions
`One case of dissiminated histoplasmosis
`
`None
`
`3–8%
`5%
`NA
`
`Nausea, dizziness, headache, fatigue
`Pyrexia, arthralgia, myalgia, headache
`Fever, neutropenia
`
`Transient rise of liver enzymes, injection-site reactions
`Transient increase of liver enzymes
`Sedation, neuropathy
`Diarrhoea, arthralgia, headache, fever, dizziness, back pain,
`anaemia, thrombocytopenia
`Injection-site reactions, fever, arthralgia, raised platelet count,
`headache, oedema, hypereosinophilia (one case)
`Only minor adverse events
`
`Headache, nausea, abdominal pain, infl uenza, hypersensitivity-
`like reactions, nasopahryngitis; progressive multifocal
`leucoencephalopathy (one per 1000 treated patients), basal cell
`carcinoma (three cases)
`Fever, chills, myalgia, arthralgia, headache, injection-site
`reactions
`
`Headache
`Similar to placebo†
`Abdominal pain and injection-site reactions; possible intestinal
`malignancy in animal studies
`
`NA
`11%
`Not applicable
`
`NA
`NA
`NA
`None
`
`None
`
`1%
`
`NA
`24%†
`NA
`
`Oedema, headache; renal adenocarcinoma (one case), benign
`schwannoma impinging on the spine (one case)
`Injection-site reactions and bone pain
`
`NA
`
`1·3%
`
`24,25
`26,27
`
`NA
`
`28
`
`29–31
`32
`33
`
`34
`35
`36
`
`37, 38
`39
`40
`41–43
`
`44–46
`
`57–62
`
`63,64
`65
`66
`
`67
`
`68–71
`
`72
`73
`
`NA
`
`

`

`New Drug Class
`
`an important intestinal growth factor.88 Studies in both
`human beings and animals have shown that recom-
`binant human growth hormone can enhance protein
`syn thesis, promote tissue recovery, and stimulate
`intestinal epi thelial growth.89,90 However, the mechanism
`underlying its protective eff ect on the intestinal mucosa
`barrier is not understood.
`
`Innate immune stimulation
`Growth factors have emerged as a new therapeutic class
`of molecules. Clinical trials investigated effi cacy and
`safety profi le of two immune stimulatory molecules:
`sargramostim,
`a
`granulocyte-macrophage
`colony-
`stimulating factor
`(GM-CSF)
`targeting neutrophils,
`monocytes, and epithelial cells; and fi lgrastim, a
`granulocyte colony-stimulating factor (G-CSF) that is
`widely used for treatment of neutropenic oncological
`patients receiving chemotherapy for malignancies, acting
`earlier in haemopoietic lineage and targeting specifi cally
`neutrophils.72 Growth hormone can also have stimulatory
`eff ects on neutrophil function.91
`
`Induction of oral tolerance
`Oral tolerance, a long-recognised method of inducing
`immune tolerance or systemic hyporesponsiveness
`induced by feeding protein, has been used to prevent or
`treat many T-cell-mediated autoimmune disorders.92
`Crohn’s disease is characterised by breakdown of
`tolerance to the intestinal bacterial fl ora,93 and feeding
`colonic extracts prevented colitis in an animal model of
`infl ammatory bowel disease.94 Therefore, induction of
`oral tolerance by feeding autologous colonic extracts can
`off er a new
`targeted
`therapy
`for patients with
`infl ammatory bowel disease.73
`
`Effi cacy of novel biological drugs in clinical trials
`T-cell blockade
`Table 1 shows the effi cacy of new biological drugs in
`clinical trials. First attempts to block CD4+ T-cell function
`with cM-T412 have failed in two open-labelled pilot studies
`enrolling 24 patients.24,45 Visilizumab has been assessed in
`both luminal and fi stulising Crohn’s disease in two
`phase I trials26,27 and in ulcerative colitis.95 Eight patients
`
`Manufacturer
`
`Mechanisms of action
`
`Compound class
`
`Other indications
`
`GW Pharmaceuticals, Salisbury, UK
`Cellerix, Madrid, Spain
`
`Cannabinoid receptor agonist
`Autologous stem-cells transplantation
`
`Small molecule (botanical extract)
`Cell therapy
`
`Rheumatoid arthritis
`
`Osiris Therapeutics, Columbia/Baltimore,
`MD, USA
`
`Ex-vivo cultured adult human mesenchymal
`stem cells
`
`Cell therapy
`
`Phase II
`THC:CBD (high CBD)
`Mesenchymal adipocyte
`stem cells/ Cx401
`Mesenchymal stem cells
`
`Phase I
`C326
`MDX-1100
`
`Avidia, Mountain View, CA, USA
`Medarex, Princeton, NJ, USA
`
`AntiVAP-1 antibody
`
`BioTie Therapies Corp, Turku, Finland
`
`Guanilib (SP-304)
`
`r-IL-18 BP
`
`Callisto Pharmaceuticals, New York, NY,
`USA
`Merck Serono SA, Geneva, Switzerland
`
`Preclinical studies
`VT-214
`VT-346
`HuMax IL-15 (AMG-714)
`
`Thymosin beta4
`IPL-42
`
`Revlimid (CC-5013)
`
`Viron therapeutics, London, ON, Canada
`Viron therapeutics, London, ON, Canada
`Genmab, Amgen, Immunex, Thousand
`Oaks, California, USA
`RegeneRx, Bethesda, MD, USA
`Infl azyme Pharmaceuticals
`LtdRichmond, BC, Canada
`Celgene Corp, Summit, NJ, USA
`
`AntiCD103 antibody
`
`LigoCyte Pharmaceuticals, Bozeman,
`MT, USA
`
`Antiβ7 antibody
`
`Genentech, South San Francisco, CA, USA
`
`IL-6 antagonist
`Chemokine IP-10 (also known as CXCL10)
`antagonist
`Human antiVAP-1 (also known as SSAO)
`antagonist
`Guanylyl cyclase receptor agonist, with