Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology,...

Injlummtory Bowel Diseuses@ 5(2):119-133 0 1999 Crohn’s & Colitis Foundation of America, Inc

Clinical Review

‘Antitumor Necrosis Factor Therapy for Inflammatory Bowel Disease: A Review of Agents, Pharmacology, Clinical Results,

and Safety,

William J.‘Sandborn and “Stephen B! Hanauer

/ - I Inflammatory Bowel Disease C U n s Division of Gastroenterology and Hepatology,r$ayo Clinic and Mayo Foundation,

Rochester, Minnesota’ and *Inflammatory Bowel Disease Center, Section of Gastroenterology, University of Chicago, Chicago, Illinois, U S A . .A

Summary: Tumor necrosis factor-a (TNFa), a proinflammatory cytokine, plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Biotechnology agents including a chimeric monoclonal anti-TNF antibody (infliximab), a humanized monoclonal anti-TNF antibody (CDP571), and a recombinant TNF receptor fusion protein (etanercept) have been used to inhibit TNFa activity. Controlled trials have demonstrated efficacy for infliximab in moderately to severely active Crohn’s disease (CD) and fistulizing CD sufficient to jus- tify recent US. Food and Drug Administration (FDA) approval. Additional trials have been completed in rheumatoid arthritis (RA). Similarly, preliminary controlled trials have suggested efficacy for CDP571 in active CD and RA. Larger controlled trials have demonstrated efficacy for etanercept in RA

patients who have failed disease modifying antirheumatic drug (DMARD) therapy leading to FDA approval for RA. Toxicities observed with anti-TNF therapies have included formation of human antichimeric antibodies (HACA) with associated acute and delayed hypersensitivity infusion reactions, human antihuman antibodies (HAHAs), and formation of autoantibodies with rare instances of drug-induced lupus. Several cases of non-Hodgkin’s lymphoma also has been described. Future studies should evaluate optimal timing and duration of anti- TNF therapy, the utility of adjuvant medical treatments during anti-TNF therapy, and evaluate long-term safety and efficacy of the various anti-TNF agents. Key Words: Antitumor necrosis factor-Antibody-Crohn’s disease-Rheumatoid arthritis- Infliximab-CDP57 1 -Etanercept.

INTRODUCTION

Current therapies for inflammatory bowel disease (IBD) are limited by low-to-moderate efficacy, delayed onset of action, frequent dosing regimens, and side effects. Medications that inhibit tumor necrosis factor-a (TNFa) have been proposed as a new therapeutic class with high efficacy, rapid onset of action, prolonged effect, and improved tolerance. This article reviews the use of anti-TNFa agents including infliximab (a chimeric monoclonal anti-TNF antibody), CDP57 1 (a humanized monoclonal anti-TNF antibody), and etanercept (a hu-

man recombinant TNF receptor fusion protein), for patients with IBD and rheumatoid arthritis (RA).

TNFa LIGAND, RECEPTORS, AND BIOLOGIC EFFECTS

The gene encoding TNFa is located on the short arm of chromosome 6, between the HLA class I and class I1 loci (1). Transcription of this gene in monocytes, macrophages, and T cells results in the secretion of inactive soluble 17 kD monomer proteins that subsequently com- bine to form 51 kD trimers, the active form of TNFa ligand (2,3). There are two different transmembrane receptors for TNFa identified on most cell types: a 55 kD protein (p55) and a 75 kD protein (p75) ( 4 3 . Circulating TNFa trimers bind to two or three TNFa receptors re-

Address correspondence and reprint requests to Dr. W. J. Sandborn,

Manuscript received January 24, i999; accepted February 4, 1999. Mayo Clinic, 200 First St., Rochester, MN15590J: U.S.A.

119

120 W. J . SANDBORN AND S. B. HANAUER

sulting in cross-linking and signal transduction (6,7). Both the p55 and p75 TNF receptors undergo enzymatic cleavage by protein kinase C at the membrane surface releasing soluble binding proteins that increase the activity of TNFa at low concentrations (due to an increased half-life of TNFa from slow release of TNFa) and inhibit TNFa activity at higher concentrations (Fig. 1) (8- 10). After binding to its membrane bound receptors, the proinflammatory cytokine TNFa mediates multiple biologic effects including recruitment of neutrophils to local sites of inflammation, induction of edema, activation of coagulation, and induction of granuloma formation (Fig. 2) (11,12).

,

ROLE OF TNFa IN IBD

TNFa has been found in the serum (13-15), stool (16,17), and intestinal tissue (18-21) of patients with IBD. The specificity remains unclear and may be com- parable to other forms of inflammation (14,15,20,21). Cells that express TNF can be found in the gut mucosa and lamina propria of Crohn's disease (CD) patients (22- 24). One study suggested enhanced secretion of TNFa and failure to release enhanced amounts of soluble TNF receptors by lamina propria mononuclear cells (25). TNFa may be a cofactor for mucosal T helper cell type 1 (Thl) response, and in a clinical study treatment with the chimeric monoclonal anti-TNFa antibody infliximab resulted in the down-regulation of mucosal Thl cytokines (26). The clinical response of patients with CD to chimeric or humanized monoclonal antibody therapy with infliximab or CDP571 reinforces the potential piv- otal role of TNFa in the pathogenesis of CD (27,28).

TNF trimer

IID

MONOCLONAL ANTIBODIES AND FUSION PROTEINS

The development of monoclonal antibody therapies has been reviewed elsewhere (29). Antibodies serve as adapters connecting antigens to effector molecules. An- tibody binding alone may provide sufficient neutralization although cell lysis via complement fixation or antibody-dependent cellular toxicity is another potential mechanism to reduce cytokine production. Attempts to therapeutically administer murine monoclonal antibodies (100% murine antibody) created using hybridoma technology resulted in significant human immune responses due to the formation of human antimouse antibodies (HAMAs) directed against the constant region of the mouse antibody (30,3 1). With repeat treatment, formation of HAMAs caused both a shortening of the half-life for the murine monoclonal antibody (due to increased clearance of the antibody from the serum) and hypersensitivity reactions (29-3 1).

Protein engineering techniques that transplant antigen binding sites from murine to human antibodies have been used to decrease amounts of murine protein in therapeutic monoclonal antibodies, thus reducing immunogenicity. The first generation of engineered monoclonal antibodies were simple chimeric monoclonal antibodies in which the variable domains of a mouse monoclonal antibody were transplanted to the constant domains of human antibodies (Fig. 3). The resulting chimeric monoclonal antibody is approximately 75% human and 25% murine (Fig. 4). While chimeric monoclonal antibodies are less immunogenic than murine monoclonal antibodies, they still result in the formation of human antichimeric antibodies (HACAs) (32) directed against the

TNF/TNF-BP comDlex

TN F TN F receptor- receptor-

trimer dimer TN F

Proteolytic 0 TNF-BP

FIG. 1. Production of soluble forms of TNF receptors (TNF-BP). TNF-BP is produced by proteolytic cleavage of transrnembrane TNF receptors (p55 and p75), e.g., as an effect of activation of protein kinase C (PKC). Re- leased TNF-BP can bind to trirneric TNF with high affinity. [Reproduced with permission from: Olsson I, Ga- tanaga T, Gullberg U, Lantz M. Granger GA. Tumor necrosis factor (TNF) binding proteins (soluble TNF receptor forms) with possible roles in inflammation and malignancy. Eur Cytokine Netw 1993;4:169-80.1

Signal Signal PKC

Inflammatory Bowel Diseases", Vol. 5, No 2, Ma) 1999

ANTI-TNF FOR IBD 121

Stirni

Cytokines, adhesion molecules, Antibodies

FIG. 2. Biological activities of tumor necrosis factor (TNF). Although several types of cells produce TNF, the main source of the cytokine is monocyte/macrophages. TNF induces a number of proinflammatory changes in endothelial cells, including cytokine production, expression of adhesion molecules, release of procoagulatory substances, and induction of iNOS. These alterations may lead to septic shock. Furthermore, TNF stimulates B and T cells, induces fever in the brain, suppresses the lipoprotein lipase in adipocytes (contributing to cachexia), and stimulates hepatocytes to produce acute phase proteins. In rheumatoid arthritis, fibroblasts and osteoclasts are target cells for TNF. INF, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase. [Reproduced with permission from: Eigler A, Sinha 8, Hartman G, Endres S. Taming TNF: strategies to restrain this proinflammatory cytokine. lmmunol Today 1997;18:487-92.1

VH VL

... 3’ - 5’ - ... 3‘ 5’ lg mRNA template lg mRNA template

4 -. ‘* .... VL /’

PCR amplification 4 of V-genes . I - E B “L.., VH ,/” ’,. /’ Cloning V-genes -., ,,/

Expression vector for

heavy chains chains

FIG. 3. Cloning of heavy and light chain V genes from the mRNA of a mouse B-cell hybridorna into vectors comprising (human) genes encoding constant domains, for expression of mousehuman chimaeric antibodies in mammalian cells. [Reproduced with permission from: Winter G, Harris WJ. Humanized antibodies. lmmunol Today 1993;14:243-6.1

transplanted variable domain from the mouse. However, these chimeric monoclonal antibodies appear to have better pharmacokinetics than murine monoclonal antibodies, with half-lives significantly extended in humans (29,33).

The second generation of engineered monoclonal antibodies were “humanized” by transplanting the antigen binding region (complimentarity determining regions or CDR) of murine variable domains to human antibodies. The resulting humanized monoclonal antibody is approximately 95% human and 5% murine (Fig. 4). While expected to be less immunogenic than chimeric monoclonal antibodies, humanized monoclonal antibodies do result in formation of human antihuman antibodies (HAHAs) directed against both the variable regions (mouse and human) and the allotype (human) antibody structures (29,34,35). Similar to chimeric monoclonal antibodies, these humanized monoclonal antibodies appear to have better pharmacokinetics than murine monoclonal antibodies, with significantly prolonged half-lives in humans (29,33).

The third generation of engineered antibodies are more properly termed “fusion proteins.” Fusion proteins are created by linking DNA encoding a human protein receptor to DNA encoding the Fc portion of a human

Inflammatory Bowel Diseases@, Vol. 5, No. 2, May 1999

122 W. J . SANDBORN A N D S. B. HANAUER

Schematic Diagram of an Antibody

Light- chain gene

Heavy- chain gene

1 n

114181 Variable Constant Constant 1

El Constant 2 E Constant 3 El Fab H Hinge

Fc

Chimeric Monoclanal

Antibody

75% human

m Mouse 0 Human

Humanized Monoclanal

Anti body

95% human

m Mouse 0 Human

CDR = Complementarity determining regions

Human Recombinant Receptor/Fc

Fusion Protein

Constant 2

Constant 3

100% human

0 Human

FIG. 4. Schematic diagrams demonstrating the structural components of antibodies and the protein engineering required to create chimeric monoclonal antibodies such as infliximab, humanized monoclonal antibodies such as CDP571, and human recombinant receptodfc fusion proteins such as the p75 TNFe receptodfc fusion protein etanercept. CDR indicates complementarity determining regions.

antibody, followed by expression of the DNA in a mammalian cell line. The resulting recombinant protein is a 100% human, immunoglobulin-like dimer (Fig. 4). Even these completely human recombinant proteins have some immunogenicity and can result in the formation of HAHAs. The fusion of the Fc portion of an antibody to soluble protein receptors significantly prolongs the half- lives of soluble receptors.

Selection of different constant domains has implica- tions for the effector function of chimeric and humanized monoclonal antibodies and fusion proteins. For example, the IgGl isotype results in complement fixation and antibody-dependent cytotoxicity whereas the IgG4 isotype has more favorable blocking characteristics.

ANTI-TNFa AGENTS AND MECHANISMS OF ACTION

Infliximab

Infliximab (previously cA2) is a chimeric monoclonal antibody to human TNFa constructed by linking the variable regions of a mouse antihuman TNF monoclonal

antibody (A2) to human IgGl with k light chains (36). It is produced commercially by Centocor (Malvern, PA, U.S.A.) and marketed as Remicade. Infliximab has a strong binding affinity to soluble trimers of TNFa (kd 100 pM) (34,37). Similarly, infliximab has a strong binding affinity to the transmembrane form of TNFa (Kd 46 pM) (38). In vitro, infliximab binding to transmembrane TNFa results in complement fixation and antibody- dependent cytotoxicity in a tumor cell line, whereas an investigational IgG4 form of infliximab showed no cell- killing activity (38). Some or all of these effects may play a role in the in vivo activity of infliximab (Fig. 5) (39). Infliximab does not promote the rapid removal of TNF, instead it paradoxically prolongs the half-life of TNFa (40). Thus infliximab acts both as a cytokine “carrier” and as a TNF antagonist, with the net effect of rendering TNF biologically inactive (40). In vivo studies with infliximab have demonstrated down regulation of mucosal Thl cytokines (26), decreased activation of coagulation (41), decreased circulating secretory phospholipase A, (42), decreased concentrations of IL-1, IL-6, soluble E-selectin, and ICAM-1 (43,44), and a decrease in serum matrix metalloproteinase 1 and matrix metalloproteinase 3 (45).

InflainmatorT). Bowel Di,waes@, V d . S, Nu 2. Muy 19%


Chimeric anti-TNF-a (infliximab) Human tzed ant t-TNF-a (CDP571) Human recombinant TNF-a p75 receptor

Fe fusion protern (Etanercept)

-inflixtmab

Neutralization of

TNF-a producing marophages or activated T cells

soluble TNF-a

-CDP571 Lysis of TF-a producing cells via complement fixation or ADCC

-infliximab

FIG. 5. Mechanisms for antibody neutralization of TNF-a. lnfliximab (chimeric anti-TNF-a antibody) works by binding to and neutralizing transmembrane TNF-a on macrophage or activated T-cell surfaces, binding to and neutralizing free TNF-cu in the serum, and lysis of TNF-a producing cells via complement fixation or antibody-dependent cellular cytotoxicity (ADCC). CDP571 (humanized anti-TNF-cu antibody) works by binding to and neutralizing free TNF-cu in the serum. Etanercept (human recombinant fusion protein with two soluble p75 TNF receptors per Fc molecule) works by binding to and neutralizing free TNF-a in the serum. [Modified and reproduced with permission from: Kam L, Targan S. lnfliximab and Crohn’s disease. Clin Persp Gastroentero/1998;1:67-72.]

CDP571

A humanized monoclonal antibody to human TNFa initially named CDP57 1 (Celltech, Slough, England, U.K.) was constructed by transplanting the complimentarity determining regions or CDR of a mouse antihuman TNF monoclonal antibody to human IgG4 with k light chains (46). CDP571 has a strong binding affinity to soluble trimers of TNFa (kd 100 pM) (29) and is believed to bind to the transmembrane form of TNFa. CDP57 1 and other investigational versions of humanized IgG4 anti-TNFa antibodies neither fix complement nor mediate antibody-dependent cytotoxicity (47). Thus, the in vivo effect of CDP571 is believed to result from the binding of soluble trimers of TNFa and membrane- bound TNFa (Fig. 5 ) (47). The only in vivo mechanistic study, to date, demonstrated a decrease in the concentration of IL-1 after treatment with CDP571 (48).

Etanercept

Etanercept (Enbrel, Immunex, Seattle, WA, U.S.A.), a human fusion protein initially named TNFR:Fc, was con-

structed by linking the extracellular ligand-binding portion of the human p75 TNF receptor to the Fc portion of IgGl (49). The Fc component contains the C,2 domain, the C,3 domain, and the hinge region but not the CH1 domain of IgGl. The fusion protein is produced by recombinant DNA technology in a Chinese hamster ovary system. The resulting fusion protein is an immunoglobulin-like dimer consisting of two soluble p75 TNF receptors per Fc molecule.

Etanercept binds soluble trimers of TNFa with the same high affinity as membrane-bound p75 TNF receptors but with a higher affinity than binding of soluble TNF trimers by soluble p75 TNF receptor monomers (49). The serum half-life of etanercept is significantly longer than the soluble p75 TNF receptor monomer (50). In vivo, etanercept competitively inhibits binding of soluble TNFa trimers to membrane bound TNFa receptors (Fig. 5) (49,51). Similar to infliximab, etanercept does not promote the rapid removal of TNF but paradoxically prolongs the half-life of TNFa by acting as a cytokine “carrier” and as a TNF antagonist, with the net effect of rendering TNF biologically inactive (51). In

Injlammatury Buwel Diseuses@, Vul. 5, No. 2, May 1999


vitro, etanercept binding to transmembrane TNFa does not result in complement fixation or antibody-dependent cytotoxicity (5 1). Mechanistic studies have demonstrated decreased concentrations of IL- 1, IL-6, soluble E- selectin, ICAM- l , and matrix metalloproteinase 3 (5 1,53) after treatment with etanercept.

PHARMACOKINETICS

Infliximab

Data from a study of single intravenous infusions of 1, 5, 10, or 20 mgkg of infliximab showed a direct and linear relationship between the dose administered and the maximum serum concentration (Cmax) and the area under the concentration-time curve (Table 1) (40,54). The median serum concentrations versus time profiles for a single i.v. infusion of 5, 10, or 20 mgkg of infliximab are shown in Fig. 6A (40). The volume of distribution at steady state (VJ, clearance, and mean residence time are independent of the administered dose (Table 1) (40,54). Infliximab is predominantly distributed in the vascular compartment and has a prolonged half-life (Table 1) (40,54). Following a single dose, the serum levels declined in an exponential fashion through 8-12 weeks (Fig. 6A). The median serum concentration of the 5 mg/ kg treatment group was undetectable by 12 weeks following the infusion. No evidence of accumulation was observed after repeated dosing with infliximab 5 mgkg at weeks 0, 2, and 6, or in after repeated dosing with 4 infusions of infliximab 10 mgkg at 8-week intervals (54).

CDP571

Data from a study of single intravenous infusions of 0.1, 0.3, 1, 2, 5, and 10 mgkg of CDP571 showed a direct and linear relationship between administered dose, maximum serum concentration (C,,,) and the area under the concentration-time curve (Table 1) (46). The mean serum concentrations versus time profiles for single i.v. infusions of 0.1,0.3, 1, 2, 5, or 10 mgkg of CDP571 are shown in Fig. 6B (46). CDP571 has a prolonged half-life and is predominantly distributed in the vascular compartment (Table 1) (46). Following a single dose, the serum levels declined in an exponential fashion through 3-12 weeks (Fig. 1). CDP571 was detectable in the serum 12 weeks after a single infusion in 7 of 12 of the subjects who received doses of 2, 5, or 10 mgkg (46).

Etanercept

Data from single subcutaneous injections of 25 mg of etanercept in 3 patients with RA showed a median half- life of 115 hours (range 98-300 hours) with a clearance of 89 &/hour (52 mL/hr/m2) (51). A maximum serum concentration (C,,,) of 1.2 mcg/& (range 0.6-1.5 mcg/ mL) and a time to C,,, of 72 hours (range 48-96 hours) was observed in these patients (51). After continued dosing in RA patients, (n = 25) for 6 months with 25 mg twice weekly, the median observed level was 3.0 mcg! mL (range 1.7-5.6 mcg/mL) (5 1). Based on the available data, individual patients may undergo two- to fivefold increase in serum levels with repeated dosing.

TABLE 1. Pharrnacokinetics of anti-TNFa agents for Crohn's disease

Dose

Parameter 0.1 mgkg 0.3 mgkg

Infliximab (Refs. 40, 54) C,,, W m L ) - - AUC (ug/mLxhr) - - V, (mL/hr) c1 (L) MRT (days) TI,, (days) CDP571 (Ref. 46) C,,, (ug/mL) 2.5 9.1 AUC (uglmLxhr) 236 1,058 T,,, (days) 5 6

- -

- - - - - -

1 mgkg 5 mgkg

- 118 - 30,900

9.8 3.0

-

- 13 10

-

-

25.5 52.7

6.9 14.3 3,968 11,184

10 mgkg

292 69,500

10.2 3 .O

12 12

166.8

11.1 26,539

20 mgkg

47 I 122,300

10.8 4.0

15 14

272.3

13.0 49,729

C,,,: Indicates maximum serum concentration. AUC: Indicates area under the concentration-time curve. V,: Indicates volume of distribution at steady state. C1: Indicates clearance. MRT: Indicates mean residence time. T,,,: Indicates half life.

Inflammatory Bowel Diseases", Vol. 5, No. 2, May 1999

ANTI-TNF FOR IBD

X = C

.- 0.1 - / I

I , I , , I I I I I 1

-Hours- Weeks b

A Time following end of infusion

1,000 4 0.1 mglkg 4 2.0 mglkg -F 5.0 mglkg Q 10.0 rnglkg

t 0.3 mgfkg -+ 1.0 rnglkg

100 2 E \ 0 10 I W

7

$ 1 a n 0.1

0.01 1 0 7 14 21 28

B Days

RESULTS IN CROHN’S DISEASE

Infliximab

The clinical studies of infliximab therapy for CD are summarized in Table 2. Infliximab was first used as a therapy for CD in a 14-year-old female with medically refractory symptoms treated with infliximab 10 mgkg at weeks 0 and 2. The patient experienced clinical and endoscopic remission lasting 3 months (55) . This initial case report was followed by a pilot study in 10 patients with medically refractory CD. Eight patients received treatment with a single infusion of infliximab 10 mgkg and 2 patients received a single infusion of infliximab 20 mgkg. All 10 patients experienced clinical and endoscopic improvement, and 9 of I0 patients experienced clinical remission lasting 8 weeks (56). Clinical improvement was accompanied by impressive endoscopic and histologic healing.

35

FIG. 6. A: The median serum concentrations versus time profiles are shown for active, moderate to severe Crohn’s disease patients (n = 25 patients per group) in reference 27 receiving a single i.v. infusion of 5, 10, or 20 mg/kg of inflixirnab. The median serum concentration was dose proportional, and remained stable through at least 4 hours following the infusion. The serum levels declined in an exponential fashion through 8-1 2 weeks following treatment. The median serum concentration of the 5 mg/kg treatment group was undetectable (C

0.1 pg/mL) by 12 weeks following the infusion. [Re- produced with permission from: Wagner C, Mace K, DeWoody K, Zelinger D, Leone A, Schaible T, She- aly D. lnfliximab treatment benefits correlate with pharmacodynamic parameters in Crohn’s disease patients. Digestion 1998;59(suppl 3):124-5.1 B: The pharmacokinetics of CDP571 in human volunteers. Elimination profiles after CDP571 was administered as a single i.v. infusion at the following doses (n = 4 per group): 0.1 mg/kg; 0.3 mg/kg; 1 mg/kg; 2 rng/kg; 5 mg/kg; or 10 mg/kg. Results are expressed as geometric means (* 95% CI). [Repro- duced with permission from: Stephens s, Emtage S, Vetterlein 0, Chaplin L, Bebbington C, Nesbitt A, Sopwith M, Athwal D, Novak C, Bodmer M. Com- prehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses. lmmunofogy f 995;85:668-74.1

The first dose-response study then enrolled 20 patients with medically refractory CD randomized to therapy with a single dose of infliximab 1 mgkg, 5 mgkg, 10 mgkg, or 20 mgkg (57). At 4 weeks, clinical improvement [defined as a decrease of at least 70 points in the Crohn’s Disease Activity Index (CDAI) score compared with the baseline value] occurred in 2 of 5 patients (40%) receiving the 1 mgkg dose, 4 of 5 (80%) at 5 mgkg, 4 of 5 (80%) at 10 mgkg, and 4 of 5 (80%) at 20 mgkg (Table 2). At 12 weeks, clinical improvement persisted in 1 of 5 patients (20%) receiving the 1 mgkg dose, 2 of 3 (67%) at 5 mgkg, 4 of 5 (80%) at 10 mgkg, and 2 of 4 (50%) at 20 mgkg. These resuits were used to determine the infliximab doses of 5 mgkg, 10 mgkg, and 20 mgkg for the Phase IIbPhase I11 placebo-controlled clinical trials.

The subsequent (Phase IIb/III) trial was designed as a randomized, double-blind, placebo-controlled, multi- center, dose-ranging study of infliximab enrolling 108

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126 W. J. SANDBORN A N D S. B. HANAUER

TABLE 2. Patient response in studies of anti-TNFa agents for Crohn ‘s disease

Indication

Placebo 1 m g k 5 mgkg 10 mgkg 20 mgkg ~ _ _ _ Reference

Response Treatment Duration I R I R I R I R I R _ _ _ ~ ~

Infliximab Derx Active

Van Dullemen Active

McCabe Active

Targan Active

Present Fistulae

Rutgeerts Remission

Van Dullemen Metastatic

(Ref. 55)

(Ref. 56)

(Ref. 57)

(Ref. 27)

(Ref. 58)

(Ref. 60)

(Ref. 59) CDP57 1

Stack Active (Ref. 28)

12 weeks

8 weeks

4 weeks

4 weeks

18 weeks

44 weeks

26 weeks

8 weeks

- - -

- -

- 4/24 17% 8/31

26% 13/37 35% -

-

511 0 50%

- - -

- -

-

1/24 4%

413 1 13% 8/37 21% -

-

0110 0%

-

-

- -

415 80% 22/27 82% 21/31 67% - - - -

1 1/20 55%

- -

- -

315 60% 13/27 48% 17/31 55% -

__ - ~

6/20 30%

111 100% 818

100% 415 80%

14/28 50% 18/32 56%

24/36 66% 111

100%

- -

111 100% 818 100% 1 15 20% 7/28 25%

12/32 38%

18/36 51% 111

100%

- -

- - 212

100% 415 80%

18/28 64% - -

- - 111

100%

- -

- - 112 50% 215 40% 7/28 25% - - -

- 01 1 0%

- -

~~~~

I: Indicates improvement as defined by a decrease in the Crohn’s disease activity index score 2 7 0 points compared with the baseline measurement for patients with active Crohn’s disease or Crohn’s disease in remission, or closure of 2 50% Crohn’s disease fistulae or metastatic perineal wounds: R, remission as defined by a Crohn’s disease activity index score <I50 points for patients with active Crohn’s disease or Crohn’s disease in remission. or closure of 100% of Crohn’s disease fistulae or metastatic perineal wounds.

patients with moderately to severely active CD refractory to medical therapy (27). Patients initially received placebo, 5 mgkg, 10 mgkg, or 20 mgkg of infliximab. At 4 weeks, clinical improvement occurred in 4 of 24 (17%) of the placebo group, 22 of 27 (82%) at 5 mg/kg, 14 of 28 (50%) at 10 mgkg, and 18 of 28 (64%) at 20 mgkg, p < 0.001 (Table 2). Clinical remission (defined as a CDAI score < 150 points) at 4 weeks occurred in 1 of 24 (4%) of the placebo group, 13 of 27 (48%) at 5 mg/kg, 7 of 28 (25%) at 10 mg/kg, and 7 of 28 (25%) at 20 mgkg, p = 0.005 (Table 2). These results confirmed that a single infusion of infliximab was effective for moderately to severely active CD refractory to medical therapy, and that 5 mgkg was the best dose for both improvement and induction of clinical remission.

A second Phase IIblIII study of infliximab was designed as a randomized, double-blind, placebo- controlled, multicenter, dose-ranging trial enrolling 94 patients with CD complicated by draining enterocutaneous fistulae involving the abdominal wall or perianal region (58). Patients were treated with three infusions of placebo or infliximab 5 mgkg or 10 mgkg at weeks 0, 2, and 6, and followed for 18 weeks. Improvement was defined as closure (in spite of gentle compression) of 250% of draining fistulae maintained for at least 4 weeks. Remission was defined as closure of all draining fistulae, maintained for at least 4 weeks. Improvement occurred in 8 of 3 1 (26%) of the placebo group, 21 of 3 1

(67%) at 5 mgkg dose, and 18 of 32 (56%) at 10 mgkg dose, p = 0.002 (Table 2). Remission of draining fistulae occurred in 4 of 31 (13%) of the placebo group, 17 of 31 (55%) after 5 mgkg dosing, and 12 of 32 (38%) after 10 mgkg dosing, p = 0.001 (Table 2). These results demonstrated that infliximab also was effective for CD complicated by draining enterocutaneous fistulae and supported 5 mg/kg as the optimal dose. Of interest, a small case series recently reported that infliximab may be useful in closing nonhealed perineal wounds in CD after proctocolectomy (59).

A preliminary maintenance of remission study was also conducted as a follow-up to the Phase IIb/III study for chronically active CD. This study was randomized, double-blind, placebo-controlled, and multi-center, enrolling 73 patients with CD in whom infliximab had been used to induce improvement or remission (60). Patients who responded to the initial dose of infliximab or placebo, or responded to a second, open label infusion of 10 mgkg were rerandomized after 12 weeks to treatment with placebo or infliximab 10 mgkg at weeks 12,20,28, and 36, and followed through 48 weeks. At 44 weeks (8 weeks after the final infliximab dose), clinical improvement was maintained in 13 of 37 (35%) of the placebo group and 24 of 36 (66%) of the 10 mgkg dosing group, p < 0.01 (Table 2). Clinical remission was maintained in 8 of 37 (21 %) of the placebo group and 18 of 36 (5 1 %) in the 10 mgkg dosing group, p < 0.05 (Table 2). How-

Injlammaror). Bowel Diseases”, Vol. 5, No. 2, May 1999


ever, because the confidence intervals were wide and the life-table analyses were not statistically significant, the results were not definitive. Nevertheless, the study sug- gests that infliximab may be effective for maintaining remission for patients who respond to an initial infusion. The optimal dose and dosing interval for infliximab maintenance of remission therapy remains to be determined. In addition, most patients were receiving concomitant therapy with aminosalicylates, steroids, or immunomodulators. Preliminary analyses suggested that concurrent immunomodulating therapy may enhance the maintenance response (Schaible T., personal communi- cation). These outcomes would be consistent with the concurrent use of immunomodulators for rheumatoid arthritis (see below). The failure to achieve statistical significance due to wide confidence intervals and questions regarding concomitant medications led the FDA to with- hold a maintenance claim for infliximab.

CDP571

A small, randomized, double-blind, placebo- controlled, multi-center Phase IIa trial with CDP571 for CD has been reported. The trial was comprised of 30 patients with mildly to severely active CD refractory to medical therapy (28). Patients were treated with a single dose of placebo or CDP571 5 mgkg and followed for 8 weeks. The primary endpoint for the study was a decrease in the median CDAI score at 2 weeks. After receiving CDP57 1, the median CDAI score decreased significantly from 263 points at baseline to 167 points at week 2, p = 0.0003; in contrast, there was no significant decrease in the median CDAI score of the placebo- treated group (253 points at baseline to 247 points) at week 2. After 2 weeks clinical remission occurred in 0 of 10 (0%) patients in the placebo group and 6 of 20 (30%) in the CDP571 5 mgkg group, p value not significant (Table 2). Of the six CDP571-treated patients who were in remission at week 2, four patients had a persistent remission for 6 weeks and three patients for 8 weeks. These results suggested that CDP571 5 mgkg may have short-term efficacy in mildly to severely active CD refractory to medical therapy. The optimal dose and dosing interval for CDP57 1 therapy for improvement, induction of remission, and maintenance for patients with CD re- main to be determined. Phase IIb/III trials for patients with CD refractory to medical therapy and for steroid- dependent patients are currently underway.

Etanercept

There are no published clinical trials of etanercept for the treatment of CD.

RESULTS IN RHEUMATOID ARTHRITIS

Infliximab

Infliximab was first used in a 20-patient pilot study for active RA that had not responded to previous therapy with various DMARDs (61). Ten patients received two infusions of infliximab 10 mgkg on days 0 and 14, and 10 patients received 4 infusions of infliximab 5 mgkg on days 0, 4, 8, and 12. All 20 patients experienced a response as determined by the Paulus 20% response criteria. Eight of these patients were entered into an open label retreatment protocol consisting of 1-3 infusions of infliximab 10 mgkg administered for relapse (defined as the loss of previous response to infliximab) (62). Seven of eight patients experienced repeated responses after 1-3 retreatment cycles, with maintenance of the response.

This initial study was followed by a 73-patient randomized, double-blind, placebo-controlled, multi-center, dose-ranging trial for active RA that had not responded to previous therapy with at least one DMARD (63). Pa- tients were randomized to a single infusion of placebo, infliximab 1 mgkg, or infliximab 10 mgkg. Clinical improvement, as determined by a Paulus 20% response criteria, occurred in 2 of 24 (8%) of the placebo group, 11 of 25 (44%) of the 1 mgkg infliximab group, and 19 of 24 (79%) of the 10 mgkg infliximab group at 4 weeks, p < 0.0001. A more stringent criteria for improvement (a Paulus 50% response) occurred in 2 of 24 (8%) of the placebo group, 7 of 25 (28%) of the 1 mgkg infliximab group, and 14 of 24 (58%) of the 10 mgkg infliximab group, p = 0.0005. These results demonstrated the efficacy of a single infusion of infliximab for active RA unresponsive to previous DMARD therapy, and that the 10 mgkg was more effective than 1 mgkg.

The next infliximab study enrolled 28 patient with active RA unresponsive to 3 months of methotrexate into a Phase IIa randomized, double-blind, placebo- controlled, multi-center, dose-ranging trial (64). Patients were randomized to a single infusion of placebo, or infliximab 5 mgkg, 10 mgkg, or 20 mgkg (64). All patients continued methotrexate 10 mglweek throughout the trial. During the course of the 12-week trial, clinical improvement, as determined by the American College of Rheumatology (ACR) response criteria, occurred in I of 7 (14%) of the placebo group compared with a pooled response of 17 of 21 (81%) for the three infliximab groups. The clinical response to infliximab tended to be more durable for patients receiving the 10 mgkg and 20 mgkg doses. Eleven of these patients were entered into an open label retreatment protocol consisting of 3 infu-

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128 W. J. SANDBORN AND S. B. HANAUER

sions of infliximab 10 mgkg administered at weeks 12, 20, and 28 (65). Nine of 11 patients experienced a prolonged response during the infliximab retreatment study. These results demonstrated that infliximab at doses of 5 mgkg, 10 mgkg, and 20 mg/kg was effective for active RA unresponsive to concurrent DMARD therapy with methotrexate and suggested that repeated dosing may be beneficial.

The first Phase IIb/III trial of infliximab in RA was a randomized, double-blind, placebo-controlled, multi- center, dose-ranging trial that enrolled 101 patients who were unresponsive to DMARD therapy with methotrexate (66). Patients were followed for 26 weeks during treatment with placebo plus methotrexate 7.5 mglweek; infliximab 1 mgkg, 3 mgkg, or 10 mgkg plus methotrexate 7.5 mg/week; or infliximab 1 mgkg, 3 mgkg, or 10 mgkg without methotrexate at weeks 0, 2, 6, 10, and 14. Improvement was defined by Paulus 20% response criteria. A durable Paulus 20% response occurred in 60% of patients treated with infliximab 3 mg/kg or 10 mg/kg, with or without methotrexate. Patients treated with infliximab 1 mgkg without methotrexate rapidly became unresponsive to repeated infliximab infusions, whereas patients treated with infliximab 1 mgkg plus methotrexate had a durable Paulus 20% response rate of 60%. These results demonstrated that repeated administration of infliximab at doses of 3 mgkg and 10 mgkg, with or without low dose methotrexate, was effective for induc- ing and maintaining a clinical response in active RA patients who were previously unresponsive to methotrexate. Efficacy of infliximab 1 mgkg required concomitant methotrexate therapy.

The second, and largest, Phase I11 infliximab study enrolled 428 patients with active RA unresponsive to methotrexate into a randomized, double-blind, placebo- controlled, multi-center, dose-ranging, multiple-dosing trial of infliximab (67). Patients were treated with placebo, infliximab 3 mgkg every 4 weeks, infliximab 3 mgkg every 8 weeks, infliximab 10 mgkg every 4 weeks, or infliximab 10 mg/kg every 8 weeks for a total of 30 weeks. All patients continued methotrexate at a dose 212.5 mg/week throughout the study. Improve- ment was defined by ACR 20 response criteria. During the course of the 30-week trial, clinical improvement occurred in 18 of 88 (20%) of the placebo group corn- pared with 43 of 86 (50%) in the 3 mgkg every 4 weeks group, 43 of 86 (50%) in the 3 mg/kg every 8 weeks group, 47 of 81 (58%) in the 10 mglkg every 4 weeks group, and 4.5 of 87 (52%) in the 10 mgkg every 8 weeks group, p < 0.001. These results demonstrated that repeated administration of infliximab was effective for in- ducing and then maintaining a clinical response in active

RA unresponsive to DMARD therapy with methotrexate, and that infliximab 3 mgkg administered every 8 weeks, in combination with methotrexate, was the optimal therapeutic strategy.

CDP571

CDP571 was first used as a therapy for RA in a 36- patient Phase IIa study for active RA that had not responded to previous therapy with various slow acting antirheumatic drugs (72). Patients were randomized to receive a single infusion of placebo or CDP571 0.1 mg/ kg, 1 mgkg, or 10 mgkg and were followed for 8 weeks. In patients receiving CDP57 1, there was a dose-related fall in the pain scale at week 1. The decrease in the pain scale for the CDP571 10 mgkg group reached a maximum decrease of 40% at 2 weeks with continued evidence of improvement at 8 weeks. Thirty of these patients then entered an open label retreatment protocol consisting of a single dose of CDP571 1 mgkg or 10 mgkg and followed for an additional 8 weeks. There were trends toward improvement at weeks 1-4 with a return to preinfusion values at week 8. The best outcomes were with placebo followed by open CDP571 10 mgkg or blinded CDP571 10 mgkg followed by open CDP571 10 mgkg. This study provides preliminary evidence that CDP57 l is efficacious for active RA and sug- gests a dose response, with the highest CDP571 dose studied to date being 10 mg/kg.

Etanercept

Etanercept was first used as a therapy for RA in a Phase I study enrolling 16 patients who had not responded to previous therapy with various DMARDs (68). Patients were randomized to receive placebo or etanercept 4 mg/m2, 8 mg/m2, 16 mg/m2, or 32 mg/m2 as an intravenous loading dose, followed by subcutaneous injections of placebo or etanercept 2 mg/m2, 4 mg/m2, 8 mg/m2, or 16 mg/m2 twice weekly for 4 weeks. Clinical improvement, as determined by improvement in total pain and total joint scores, occurred in 22% of placebo- treated patients and 4.5% of etanercept-treated patients. There was no clear evidence of a dose response.

This Phase I study was followed by a Phase I1 study of 180 patients with active RA who had not responded to previous therapy with various DMARDs (69). Patients were randomized to receive a twice-weekly course of subcutaneous injections of placebo or etanercept 0.25 mg/m2, 2 mg/m2, or 16 mg/m2. Clinical improvement as determined by ACR 20 response criteria at 12 weeks occurred in 14% of the placebo group, 33% of the etaner-

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cept 0.25 mg/m2 group, 46% of the etanercept 2 mg/m2 group, and 75% of the etanercept 16 mg/m2 group. These results demonstrated that etanercept at twice-weekly doses of 0.25 mg/m2, 2 mg/m2, and 16 mg/m2 was effective for up to 12 weeks in patients with active RA who had not responded to previous therapy with various DMARDs, and that 16 mg/m2 was the most effective etanercept dose.

A larger, 234-patient Phase I11 randomized, double- blind, placebo-controlled, multi-center, dose-ranging, multiple-dosing trial of etanercept was held for active RA patients who had not responded to previous therapy with various DMARDs (70). Patients were treated with placebo, etanercept 10 mg, or etanercept 25 mg (equivalent to 16 mg/m2) twice weekly as a subcutaneous injection for 6 months. Improvement was defined by ACR 20 response criteria. During the course of the 6-month trial, clinical improvement occurred in 23% of the placebo group, 46% of the etanercept 10 mg group, and 62% of the etanercept 25 mg group. These results demonstrated that etanercept at twice-weekly doses of 10 mg and 25 mg was effective for up to 6 months in patients with active RA who had not responded to previous therapy with various DMARDs, and that the 25-mg etanercept dose was most effective.

The second Phase I11 trial was a randomized, double- blind, placebo-controlled, multi-center, multiple-dosing trial of etanercept enrolling 89 patients with active RA unresponsive to DMARD therapy with methotrexate (71). Patients were treated with placebo or etanercept 25 mg (equivalent to 16 mg/m2) twice weekly as a subcutaneous injection for 6 months. All patients continued methotrexate throughout the study. Improvement was defined by ACR 20 response criteria. During the course of the 6-month trial, clinical improvement occurred in 27% of the placebo group and 71% of the etanercept group. These results demonstrated that etanercept at a twice- weekly dose of 25 mg was more effective than placebo for up to 6 months in active RA patients who were unresponsive to DMARD therapy with methotrexate.

RESULTS IN ULCERATIVE COLITIS

Infliximab

A preliminary Phase IIa trial with infliximab for ulcerative colitis (UC) had been reported. The study enrolled 1 1 hospitalized patients with severely active, steroid-refractory UC treated in a randomized, double- blind, placebo-controlled, multi-center trial (73). Patients were treated with a single dose of placebo or infliximab 5 mgkg, 10 mgkg, or 20 mg/kg and followed for 2

weeks. The primary endpoint for the study was clinical response as defined by a decrease in the baseline modified Truelove and Witt's score of 2 5 points and an ab- solute score c 10 points. At 2 weeks a clinical response was observed in 0 of 3 patients in the placebo group, 2 of 3 patients in the infliximab 5 mgkg group, 1 of 3 patients in the infliximab 10 mgkg group, and 2 of 2 patients in the infliximab 20 mgkg group. These findings provide preliminary evidence that infliximab may be of benefit in severe UC, but additional studies are needed to prove efficacy and to determine optimal dose and dosing intervals.

CDP571

A Phase I, open-label trial with CDP571 for UC has been reported from a single center (74). Fifteen patients with mildly to moderately active UC, some of whom were refractory to medical therapy, were treated with a single dose of CDPS71 5 mgkg and followed for 8 weeks. The primary endpoint was a decrease in the mean Powell Tuck score over the course of the study. The mean Powell Tuck score decreased significantly from 6.7 to 4.6 points at week 1, and there was a trend towards a decreased score at week 2 but not at weeks 4 or 8. These results suggest a possible short-term benefit from CDP57 1, 5 mgkg (up to 2 weeks) in mildly to moderately active UC. Additional studies are needed to prove efficacy and to determine the optimal dose and dosing interval. Of interest, CDPS71 has also shown benefit in the cotton-top tamarin animal model of UC (75).

E tanercep t

There are no published clinical trials of etanercept for the treatment of UC.

TOXICITY OF ANTI-TNFa THERAPY

Immunogenicity (Formation of HACA or HAHA)

One hundred thirty-four of 199 CD patients treated with infliximab were evaluated for the presence of antibodies to infliximab (HACAs), of whom 18 (13%) were positive (54). HACA-positive patients were more likely to experience infusion reactions. Concomitant immune modifier therapy with corticosteroids, azathioprine, or 6-mercaptopurine during infliximab therapy for CD appeared to protect- against HACA formation (10% frequency) compared with patients not taking immune modifier therapy (23% frequency) (54). Similarly, low- dose methotrexate (7.5 mg/week) during infliximab

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I30 W. J. SANDBORN A N D S. B. HANAUER

therapy for RA protected against HACA formation (66). Of note, higher doses of infliximab (25 mgkg) may be associated with less HACA formation than lower doses of 1 mgkg or 3 mgkg (66). The presence of HACA may be associated with an increased clearance and shortened serum half-life of infliximab (62). At present there is no commercially available assay for HACA.

Sixteen percent of patients treated with etanercept for RA developed antibodies to etanercept (HAHAs) that did not correlate with clinical response or adverse events ( 5 1). The likelihood of developing antibodies to CDP571 (HAHAs) in healthy volunteers treated with CDP57 1 was inversely proportional to the dose, with minimal HAHA formation at the 10 mgkg dose (46). Seven of 20 (35%) patients with CD treated with CDP57 I developed a HAHA response (28). The clinical significance of HAHA antibodies after CDP571 is unknown.

Autoantibodies

Eighty-five of 357 (24%) of infliximab-treated patients evaluated for antinuclear antibodies (ANA) were positive at baseline compared with 128 of 357 (36%) at the last evaluation (54).

Antidouble stranded DNA (anti-dsDNA) developed in approximately 9% of patients treated with infliximab. Baseline therapy with immune modifier therapy in CD was associated with a decreased likelihood of developing anti-dsDNA (3% versus 21%) (54). Two patients treated with infliximab developed clinical symptoms consistent with a lupus-like syndrome requiring discontinuation of infliximab and treatment with corticosteroids. Anti- dsDNA disappeared when infliximab therapy was dis- continued.

Whether patients treated with CDP571 have an increased frequency of new autoantibody formation is unknown.

Patients treated with etanercept do have an increased frequency of developing new autoantibodies compared with placebo-treated patients: ANA, 11% versus 5%; anti-dsDNA, 15% versus 4% (51).

Infusion-Related Reactions

Among 1,207 infliximab infusion reactions (defined as any adverse event occurring during or for 2 hours after an infusion), 58 of 1,207 (5%) were accompanied by non- bpecific symptoms such as fever or chills. One percent were accompanied by pruritus or urticaria, 1% by cardiopulmonary reactions (primarily chest pain, hypoten- sion, hypertension, or dyspnea), and 0.2% by combined symptoms of pruritushrticaria and cardiopulmonary re-

actions (54). Infusion reactions were more likely during a second infusion. Patients who became positive for HACA were more likely to develop infusion reactions (36% versus 1 I%), and concomitant therapy with immune modifier therapy appeared to reduce the frequency of infusion reactions.

Recently, the manufacturer of infliximab (Centocor) reported that 10 of 40 (25%) patients with CD treated 2-4 years previously with infliximab developed a serum sickness-like, delayed-hypersensitivity reaction 3-12 days after retreatment. Signs and symptoms included myalgia, rash, fever, polyarthralgia, pruritus, facial or lip edema, dysphagia, and urticaria. Six of the 10 patients were hospitalized and were treated with high-dose steroids. These patients had been negative for HACA at the time of retreatment but, at the time of the reaction, had developed titers as high as 1:40,000 and were found to have no circulating infliximab, suggesting a rapid anem- nestic response with antigen-antibody complex formation.

The frequency, types, and severity of infusion reactions after treatment with CDP571 is unknown, although in studies reported to date this issue does not appear to be a significant problem (28,46,72,74).

Thirty-seven percent of patients treated with etanercept developed reactions at injection sites (51). All injection site reactions were described as mild to moderate (erythema, and/or itching, pain, or swelling) and gener- ally did not necessitate drug discontinuation.

Lymphoproliferative Disorders

Of 394 patients treated with infliximab who were followed from 6 months to 3 years after receiving their last infusion, one case of non-Hodgkin's lymphoma (NHL) was identified in a CD patient, two cases of NHL were observed in patients with RA, and one case of NHL occurred in a patient with HIV and AIDS (54). In addition, one case of myeloma occurred in a patient with RA. Subsequently one additional case of NHL occurred in an infliximab-treated RA patient participating in a multiple- dosing study in which 340 patients received infliximab (67). Given the confounding associations between NHI, and both RA (76) and AIDS (77), the available data are not sufficient to determine whether there is an increased risk of NHL after exposure to infliximab. An association between NHL and CD is less clear cut, with one study reporting a series of nine cases (78) but three population- based studies reporting no evidence for a statistically increased risk (79-81).

To date, with only 166 patients or healthy volunteers reported treated with single or multiple doses of

lnflurnrnutory Bowel Diseuserm, Vol. 5, No. 2, May I Y Y Y


CDP57 1, no lymphoproliferative disorders have occurred.

Among 745 RA patients treated in clinical trials with etanercept for up to 18 months, one case of Hodgkin’s disease and no cases of NHL occurred.

It is unclear whether NHL occurring after infliximab for CD and RA, as compared with etanercept and CDP571, is a true increased risk or simply represents imprecise confidence intervals.

Infections and Abscesses

There is no evidence of an increased frequency of serious infections associated with infliximab, etanercept, or CDP57 1 compared with placebo-treated patients (27, 46,51,54,72,74). There was a 12% frequency of new ab- scess formation among patients with fistulizing CD treated with infliximab, possibly due to uneven healing of fistula tracts, with closure of the cutaneous opening before healing of the mucosal orifice.

CONCLUSIONS

Biotechnology agents including infliximab, CDP57 1, and etanercept have been used to inhibit TNFa activity. Controlled trials have demonstrated efficacy for infliximab in moderately to severely active CD and fistulizing CD with sufficient evidence of safety and efficacy for recent FDA approval. Regulatory assessment of infliximab for RA is pending. Similarly, the FDA has accepted the demonstrated efficacy and safety for etanercept in RA patients who have failed disease DMARD therapy. Preliminary controlled trials have demonstrated efficacy for CDP571 in active CD and RA. Toxicities observed with biologic anti-TNF therapies have included formation of HACAs and HAHAs, leading in some instances to minor and severe infusion reactions, and formation of autoantibodies leading in some instances to drug-induced lupus. The true risk of NHL remains to be determined after larger populations are studied over longer periods of time. Future studies should evaluate the optimal timing and duration of anti-TNF therapy, the utility of con- tinuing other medical treatments during anti-TNF therapy, and should compare the safety and efficacy of the biologic and soon to be evaluated standard pharma- cologic approaches to inhibit TNF such as thalidomide.

1.

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