Remicade (Infliximab) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

GENERAL

Infliximab neutralizes the biological activity of TNF(alpha) by binding with high affinity to the soluble and transmembrane forms of TNF(alpha) and inhibits binding of TNF(alpha) with its receptors. ^2,3 Infliximab does not neutralize TNF(beta) (lymphotoxin (alpha)), a related cytokine that utilizes the same receptors as TNF(alpha). Biological activities attributed to TNF(alpha) include: induction of pro-inflammatory cytokines such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes. Cells expressing transmembrane TNF(alpha) bound by infliximab can be lysed in vitro ³ or in vivo.⁴ Infliximab inhibits the functional activity of TNF(alpha) in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T lymphocytes and epithelial cells. Anti-TNF(alpha) antibodies reduce disease activity in the cotton-top tamarin colitis model, and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab prevents disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNF(alpha), and when administered after disease onset, allows eroded joints to heal.

PHARMACODYNAMICS

Elevated concentrations of TNF(alpha) have been found in the joints of rheumatoid arthritis patients and the stools of Crohn's disease patients and correlate with elevated disease activity. In rheumatoid arthritis, treatment with REMICADE reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion [E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)], chemoattraction [IL-8 and monocyte chemotactic protein (MCP-1)] and tissue degradation [matrix metalloproteinase (MMP) 1 and 3]. In Crohn's disease, treatment with REMICADE reduced infiltration of inflammatory cells and TNF(alpha) production in inflamed areas of the intestine, and reduced the proportion of mononuclear cells from the lamina propria able to express TNF(alpha) and interferon. After treatment with REMICADE, patients with rheumatoid arthritis or Crohn's disease exhibited decreased levels of serum IL-6 and C-reactive protein (CRP) compared to baseline. Peripheral blood lymphocytes from REMICADE-treated patients showed no significant decrease in number or in proliferative responses to in vitro mitogenic stimulation when compared to cells from untreated patients.

PHARMACOKINETICS

Single intravenous (IV) infusions of 3 mg/kg to 20 mg/kg showed a linear relationship between the dose administered and the maximum serum concentration. The volume of distribution at steady state was independent of dose and indicated that infliximab was distributed primarily within the vascular compartment. Median pharmacokinetic results for doses of 3 mg/kg to 10 mg/kg in rheumatoid arthritis and 5 mg/kg in Crohn's disease indicate that the terminal half-life of infliximab is 8.0 to 9.5 days.

Following an initial dose of REMICADE, repeated infusions at 2 and 6 weeks resulted in predictable concentration-time profiles following each treatment. No systemic accumulation of infliximab occurred upon continued repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals. No major differences in clearance or volume of distribution were observed in patient subgroups defined by age, weight, or gender. It is not known if there are differences in clearance or volume of distribution in patients with marked impairment of hepatic or renal function.

A pediatric Crohn's disease pharmacokinetic study was conducted in 21 patients aged 11 to 17 years old. No notable differences in single-dose pharmacokinetic parameters were observed between pediatric and adult Crohn's disease patients (see PRECAUTIONS, Pediatric Use).

CLINICAL STUDIES

RHEUMATOID ARTHRITIS

The safety and efficacy of REMICADE when given in conjunction with methotrexate (MTX) were assessed in a multicenter, randomized, double-blind, placebo-controlled study of 428 patients with active rheumatoid arthritis despite treatment with MTX (the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy or ATTRACT). Patients enrolled had a median age of 54 years, median disease duration of 8.4 years, median swollen and tender joint count of 20 and 31 respectively, and were on a median dose of 15 mg/wk of MTX. Patients received either placebo + MTX or one of 4 doses/schedules of REMICADE + MTX: 3 mg/kg or 10 mg/kg of REMICADE by IV infusion at weeks 0, 2 and 6 followed by additional infusions every 4 or 8 weeks in combination with MTX. Concurrent use of stable doses of folic acid, oral corticosteroids (</=10 mg/day) and/or nonsteroidal anti-inflammatory drugs was also permitted.

Data on use of REMICADE without concurrent MTX are limited (see ADVERSE REACTIONS, Immunogenicity).^5,6

Clinical response

All doses/schedules of REMICADE + MTX resulted in improvement in signs and symptoms as measured by the American College of Rheumatology response criteria (ACR 20) with a higher percentage of patients achieving an ACR 20, 50 and 70 compared to placebo + MTX (Table 1). This improvement was observed at week 2 and maintained through week 102. Greater effects on each component of the ACR 20 were observed in all patients treated with REMICADE + MTX compared to placebo + MTX (Table 2). Approximately 10% of patients treated with REMICADE achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6-month period compared to 0% of placebo-treated patients (p</=0.018).

Radiographic response

Structural damage in both hands and feet was assessed radiographically at week 54 by the change from baseline in the van der Heijde-modified Sharp score, a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet. ⁷ Approximately 80% of patients had paired x-ray data at 54 weeks and approximately 70% at 102 weeks. The inhibition of progression of structural damage was observed at 54 weeks (Table 3) and maintained through 102 weeks.

Physical function response

Physical function and disability were assessed using the Health Assessment Questionnaire (HAQ) and the general health-related quality of life questionnaire SF-36. All doses/schedules of REMICADE + MTX showed significantly greater improvement from baseline in HAQ and SF-36 physical component summary score averaged over time through week 54 compared to placebo + MTX, and no worsening in the SF-36 mental component summary score.

The median (interquartile range) improvement from baseline to week 54 in HAQ was 0.1 (-0.1, 0.5) for the placebo + MTX group and 0.4 (0.1, 0.9) for REMICADE + MTX (p<0.001). Both HAQ and SF-36 effects were maintained through week 102. Approximately 80% of patients in all doses/schedules of REMICADE + MTX remained in the trial through 102 weeks.

ACTIVE CROHN'S DISEASE

The safety and efficacy of single and multiple doses of REMICADE were assessed in two randomized, double-blind, placebo-controlled clinical studies in 653 patients with moderate to severely active Crohn's disease [Crohn's Disease Activity Index (CDAI) >/=220 and </=400] with an inadequate response to prior conventional therapies. Concomitant stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents were permitted and 92% of patients continued to receive at least one of these medications.

In the single-dose trial⁸ of 108 patients, 16% (4/25) of placebo patients achieved a clinical response (decrease in CDAI >/=70 points) at week 4 vs. 81% (22/27) of patients receiving 5 mg/kg REMICADE (p<0.001, two-sided, Fisher's Exact test). Additionally, 4% (1/25) of placebo patients and 48% (13/27) of patients receiving 5 mg/kg REMICADE achieved clinical remission (CDAI<150) at week 4.

In a multidose trial (ACCENT I)⁹, 545 patients received 5 mg/kg at week 0 and were then randomized to one of three treatment groups; the placebo maintenance group received placebo at weeks 2 and 6, and then every 8 weeks; the 5 mg/kg maintenance group received 5 mg/kg at weeks 2 and 6, and then every 8 weeks; and the 10 mg/kg maintenance group received 5 mg/kg at weeks 2 and 6, and then 10 mg/kg every 8 weeks. Patients in response at week 2 were randomized and analyzed separately from those not in response at week 2. Corticosteroid taper was permitted after week 6.

At week 2, 57% (311/545) of patients were in clinical response. At week 30, a significantly greater proportion of these patients in the 5 mg/kg and 10 mg/kg maintenance groups achieved clinical remission compared to patients in the placebo maintenance group (Table 4).

Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg infliximab maintenance groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo maintenance group at week 54 (Table 4).

Patients in the infliximab maintenance groups (5 mg/kg and 10 mg/kg) had a longer time to loss of response than patients in the placebo maintenance group (Figure 1). At weeks 30 and 54, significant improvement from baseline was seen among the 5 mg/kg and 10 mg/kg infliximab-treated groups compared to the placebo group in the disease specific inflammatory bowel disease questionnaire (IBDQ), particularly the bowel and systemic components, and in the physical component summary score of the general health-related quality of life questionnaire SF-36.

In a subset of 78 patients who had mucosal ulceration at baseline and who participated in an endoscopic substudy, 13 of 43 patients in the infliximab maintenance group had endoscopic evidence of mucosal healing compared to 1 of 28 patients in the placebo group at week 10. Of the infliximab-treated patients showing mucosal healing at week 10, 9 of 12 patients also showed mucosal healing at week 54.

Patients who achieved a response and subsequently lost response were eligible to receive infliximab on an episodic basis at a dose that was 5 mg/kg higher than the dose to which they were randomized. The majority of such patients responded to the higher dose. Among patients who were not in response at week 2, 59% (92/157) of infliximab maintenance patients responded by week 14 compared to 51% (39/77) of placebo maintenance patients. Among patients who did not respond by week 14, additional therapy did not result in significantly more responses (see DOSAGE AND ADMINISTRATION).

FISTULIZING CROHN'S DISEASE

The safety and efficacy of REMICADE were assessed in 2 randomized, double-blind, placebo-controlled studies in patients with fistulizing Crohn's disease with fistula(s) that were of at least 3 months duration. Concurrent use of stable doses of corticosteroids, 5-aminosalicylates, antibiotics, MTX, 6-mercaptopurine (6-MP) and/or azathioprine (AZA) was permitted.

In the first trial,¹⁰ 94 patients received three doses of either placebo or REMICADE at weeks 0, 2 and 6. Fistula response (>/=50% reduction in number of enterocutaneous fistulas draining upon gentle compression on at least two consecutive visits without an increase in medication or surgery for Crohn's disease) was seen in 68% (21/31) of patients in the 5 mg/kg REMICADE group (p=0.002) and 56% (18/32) of patients in the 10 mg/kg REMICADE group (p=0.021) vs. 26% (8/31) of patients in the placebo arm. The median time to onset of response and median duration of response in REMICADE-treated patients was 2 and 12 weeks, respectively. Closure of all fistula was achieved in 52% of REMICADE-treated patients compared with 13% of placebo-treated patients (p<0.001).

In the second trial (ACCENT II), patients who were enrolled had to have at least one draining enterocutaneous (perianal, abdominal) fistula. All patients received 5 mg/kg REMICADE at weeks 0, 2 and 6. Patients were randomized to placebo or 5 mg/kg REMICADE maintenance at week 14. Patients received maintenance doses at week 14 and then every eight weeks through week 46. Patients who were in fistula response (fistula response was defined the same as in the first trial) at both weeks 10 and 14 were randomized separately from those not in response. The primary endpoint was time from randomization to loss of response among those patients who were in fistula response.

Among the randomized patients (273 of the 296 initially enrolled), 87% had perianal fistulas and 14% had abdominal fistulas. Eight percent also had rectovaginal fistulas. Greater than 90% of the patients had received previous immunosuppressive and antibiotic therapy.

At week 14, 65% (177/273) of patients were in fistula response. Patients randomized to REMICADE maintenance had a longer time to loss of fistula response compared to the placebo maintenance group (Figure 2). At week 54, 38% (33/87) of REMICADE-treated patients had no draining fistulas compared with 22% (20/90) of placebo-treated patients (p=0.02). Compared to placebo maintenance, patients on REMICADE maintenance had a trend toward fewer hospitalizations.

Figure 2
Life table estimates of the proportion of patients who had not lost fistula response through week 54

Patients who achieved a fistula response and subsequently lost response were eligible to receive REMICADE maintenance therapy at a dose that was 5 mg/kg higher than the dose to which they were randomized. Of the placebo maintenance patients, 66% (25/38) responded to 5 mg/kg REMICADE, and 57% (12/21) of REMICADE maintenance patients responded to 10 mg/kg.

Patients who had not achieved a response by week 14 were unlikely to respond to additional doses of REMICADE.

Similar proportions of patients in either group developed new fistulas (17% overall) and similar numbers developed abscesses (15% overall).