Biologics for Use in Crohns Disease

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There are a number of therapeutic targets for new biologics in CD (Fig. 12.4). Biologics aim to reduce muco-sal inflammation by inhibiting the effects of proinflam-matory cytokines [interleukin (IL)-1|3, TNF, IFN-y, IL-12, IL-18], by inducing apoptosis of type 1 helper lymphocytes (anti-IL-6, TNF antagonists), or by boosting natural anti-inflammatory mechanisms (granulocyte-macrophage colony-stimulating factor, transforming growth factor-|3, IL-20) (van Deventer 2003). Table 12.1 provides a list of approved and potential future biologic therapies for CD and key clinical trial data are summarized in Table 12.2.

Fig. 12.4.
Table 12.1. Evolving and approved biologics for Crohn's disease and ulcera-tive colitis

1 Therapeutic approach

Agent

Target

Phase

Indication 1

Pro-inflammatory cytokines/

Adalimumab

TNF

3

CD

pathways

Infliximab

TNF

4a

CD/UC

Certolizumab

TNF

3

CD

Fontolizumab

IFN

2

CD

Selective adhesion molecules

MLN-02 (LDP-02)

3

UC/CD

Natalizumab

a4

3

CD

T-cell differentiation/subsets

ABT-874

IL-12/IL-23

2a

CD

Basiliximab

IL-2R

2

UC

CNTO 1275

IL-12/IL-23

2

CD

Daclizumab

IL-2R

2

UC

Visilizumab

CD3

2-3

UC

MRA

IL-6R

2

CD

Innate immune stimulation

GM-CSF

GM-CSF-R

3

CD

Intestinal repair

EGF

EGF-R

3

UC

Growth hormone

hGH-R

2

CD

a Approved for use by the US Food and Drug Administration and the European Agency for the Evaluation of Medical Products for the treatment of Crohn's disease and ulcerative colitis

CD Crohn's disease, EGF epidermal growth factor, EGF-R epidermal growth factor receptor, GM-CSF granulocyte-macrophage colony-stimulating factor, GM-CSF-R granulocyte-macrophage colony-stimulating factor receptor, hGH-R human growth hormone receptor, IFN interferon, IL interleukin, TNF tumor necrosis factor, UC ulcerative colitis

Table 12.2. Summary of clinical data for each biologic in Crohn's disease

Trial name

Treatment

N

Study Primary endpoint(s)

Secondary endpoints

duration

Adalimumab

CLASSIC I (Hanauer et al. 2006)

CLASSIC II (Sandborn et al. 2005)

CHARM (Colombel et al. submitted to DDW 2 006)

Adalimumab (160/80 mg, 80/40 mg, 40/20 mg) Placebo

Adalimumab 40 mg e.o.w.

Induction:

Adalimumab 80 mg at Week 0 and 40 mg at Week2 Maintenance: Adalimumab 40 mg e.o.w., 40 mg weekly, or placebo

Certolizumab pegol

PRECiSE-2 Induction: (Schreiber Certolizumab 400 mg at 2005) Weeks 0,2, and 4

Maintenance: Certolizumab 400 mg or placebo q4 weeks

PRECiSE-1 Induction: (Sandborn Certolizumab 400 mg or et al. 2006) placebo at Weeks 0, 2, and 4

Maintenance: Certolizumab 400 mg or placebo q4 weeks

Infliximab

ACCENT I Induction with infliximab (Hanauer 5 mg/kg at Week 0 et al. 2002) Group 1:

Placebo at Weeks 2, 6 and q8 weeks Group 2:

Infliximab 5 mg/kg at Weeks 2, 6, and q8 weeks Group 3:

Infliximab 5 mg/kg at Weeks 2,6, and 10 mg/kg q8 weeks

ACCENT II Induction: (Sands et al. Infliximab 5 mg/kg at 2004) Week 0, 2, and 6

Maintenance: Infliximab 5 mg/kg or placebo q8 weeks

221 in OL cohort; 55 in RCT arm

260 257 261

216 212

331 328

4 weeks

4weekOL segment then 52 week RCT or OL arm

56 weeks

26 weeks

26 weeks

54 weeks

Clinical remission (CDAI < 150) at Week 4: 36%, 24%, 18% vs. 12%

Clinical remission (CDAI < 150) at Week 56: 43% in OL cohort

Clinical remission (CDAI <150) at Week 26: 40%, 46% vs. 17% (p<0.001) Clinical remission (CDAI <150) at Week 56: 36%, 41% vs. 12% (p<0.001)

Clinical response (CDAI

100) among CRP >10 mg/l stratum: 62% vs. 34% (p<0.001)

Clinical response (CDAI > 100) at Week 6 among CRP > 10 mg/l stratum: 37% vs. 26% (p<0.05) Clinical response (CDAI 100) at Weeks 6 and 26 among CRP > 10 mg/l stratum: 22% vs. 12% (p< 0.05)

CDAI > 70: 59 %, 59 %, 54% vs. 37% CDAI > 100: 50 %, 40 %, 34 % vs. 25 %

Clinical remission (CDAI 150) + discontinuation of steroids: 29 % (p <0.001), 23% (p = 0.008) vs. 6% Complete fistula closure: 36 %, 46 %, vs. 14% (p<0.027)

Clinical remission (CDAI < 150)

Clinical response among ITT: 63%

Clinical remission (CDAI 150)

Clinical remission (CDAI < 150) at Week 6 among CRP > 10 mg/l stratum: 22% vs. 17% Clinical remission (CDAI < 150) at Weeks 6 and 26 among CRP > 10 mg/l stratum: 13% vs. 8% Clinical remission (CDAI < 150) at Week 6 among ITT: 22 % vs. 17% Clinical remission (CDAI < 150) at Weeks 6 and 26 among ITT: 14% vs. 10%

54 weeks Clinical remission (CDAI Clinical remission (CDAI <150) at

<150) at Week 30: 39% (p = 0.022), 46% (p = 0.001) vs. 25% Median time to loss of response up to Week 54: 37 weeks, >54 weeks vs. 19 weeks

Median time to loss of response: >40 weeks vs. 14 weeks (p <0.001)

Week 54 + discontinuation of steroids: 25% (p = 0.059), 34% (0.005) vs. 11%

Mucosal healing at Week 10: 13 of 43 patients in infliximab groups vs. 1 of 28 in placebo group

No draining fistulas at Week 54: 365 vs. 19% (p = 0.009)

96 99

Table 12.2. (Cont.)

Trial name

Treatment

N

Study Primary endpoint(s)

Secondary endpoints

duration

REACH (Cuc- Induction:

10 weeks 54 weeks

Clinical response (PCDAI > 15 and PCD AI <30) at Week 10: 88%

REACH (Cuc- Induction:

cuiara et al. 2006; Hyams et al. 2006)

Natalizumab

ENACT-1 (Sandborn et al. 2005c)

Infliximab 5 mg/kg at Weeks 0,2, and 6 Maintenance: Infliximab q8 weeks or q12 weeks through Week 46

Induction:

Natalizumab 300 mg or placebo at Weeks 0, 4, and 8

52 51

10 weeks 54 weeks

Clinical response (PCDAI > 15 and PCD AI <30) at Week 10: 88%

724 181

3 months

Clinical response (CDAI >70) at Week 10:56% vs. 49%

Clinical remission (CDAI <150) at Week 10: 37% vs. 30%

Natalizumab 300 mg q4 weeks or placebo

ENACT-2 (Sandborn et al. 2005c)

Anti-IL-12 Antibody (ABT-874) Mannon et al. Cohort 1: 2004

ABT-874:1 mg/kg, 3 mg/kg, or placebo for 7 injections, with a 4-week interval between injection 1 and 2 and weekly intervals between the remaining doses (last dose at Week 9) Cohort 2:

ABT-874 1 mg/kg, 3 mg/kg, or placebo weekly for 7 weeks (last dose at Week 7)

168 170

16 16 8

12 months Clinical response at

6 months of maintenance (9 months of therapy)

18 weeks Safety: Rates of adverse events similar among ABT-874 and placebo, except in local reactions at injection site Cohort 1: 75%, 81% vs. 38%

Cohort 2: 80%, 94% vs. 12% (p <0.005 vs. placebo)

16 8

Sargramostim (granulocyte-macrophage colony-stimulating factor)

Korzenik et al. Sargramostim 57 days Clinical response (CDAI

placebo

Clinical response (PCDAI > 15 and PCDAI <30) at Week 54: 63% in the q8 week group versus 33% in the q12 week group

Clinical remission (PCDAI <10) at Week 54: 56 % in the q8 week group versus 24% in the q12 week group Median change in average daily corticosteroid dose at Weeks 10, 30, and 54: -0.2, -0.3, and -0.3 mg/kg/day

Clinical response (CDAI >70) at Week 12: 61% vs. 51% (p = 0.009) Clinical remission among patients with CRP >2.87 mg/l: 40% vs. 28% (p = 0.014)

Clinical remission among patients failing immunosuppressants: 40 % vs. 25% (p = 0.041)

Clinical remission among patients with CRP >2.87 mg/l and failing immunosuppressants: 41% vs. 18% (p = 0.011)

Clinical response (CDAI > 100): Cohort 1:

Week 4: 50%, 19% vs. 13% Week 9: 63%, 56% vs. 38% Week 18: 19%, 50% vs. 25% Cohort 2:

Week 7: 27%, 75% vs. 25% (p = 0.03 for 3 mg/kg vs. placebo) Week 18: 20%, 69% vs. 25% Clinical remission (CDAI <150): Cohort 1:

Week 4: 19 %, 12 % vs. 0 % Week 9: 31%, 44% vs. 38% Week 18: 19%, 50% vs. 13% Cohort 2:

Clinical response (CDAI > 100): 48% vs. 26% (p = 0.01)

Clinical remission (CDAI <150): 40% vs. 19% (p = 0.01)

ACCENT A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen, CDAI Crohn's Disease Activity Index, CHARM Crohn's Trial of the Fully Human Antibody Adalimumab for Induction and Remission Maintenance, CLASSIC Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease, CRP C-reac-tive protein, e.o.w. every other week, ENACT Efficacy of Natalizumab as Active Crohn's Therapy, ITT intention-to-treat, OL open-label, PCDAI Pediatric Crohn's Disease Activity Index, q every, REACH Randomized, Multicenter, Open-label Study to Evaluate the Safety and Efficacy of Anti-TNF Monoclonal Antibody Remicade in Pediatric Subjects with Moderate to Severe Crohn's Disease

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