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Mechanism of Action

Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα. This interaction prevents the binding of TNFα to its receptors, thereby inhibiting the biological activity of TNFα (a cytokine protein). There was no evidence of the golimumab antibody binding to other TNF superfamily ligands; in particular, the golimumab antibody did not bind or neutralize human lymphotoxin. Golimumab did not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells. Elevated TNFα levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNFα is an important mediator of the articular inflammation that is characteristic of these diseases. Golimumab modulated the in vitro biological effects mediated by TNF in several bioassays, including the expression of adhesion proteins responsible for leukocyte infiltration (E-selectin, ICAM-1 and VCAM-1) and the secretion of proinflammatory cytokines (IL-6, IL-8, G-CSF and GM-CSF).

Pharmacodynamics

In clinical studies, decreases in C-reactive protein (CRP), interleukin (IL)-6, matrix metalloproteinase 3 (MMP-3), intercellular adhesion molecule (ICAM)-1 and vascular endothelial growth factor (VEGF) were observed following SIMPONI (golimumab injection) administration in patients with RA, PsA, and AS.

Pharmacokinetics

Following subcutaneous (SC) administration of SIMPONI (golimumab injection) to healthy subjects and patients with active RA, the median time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. A SC injection of 50 mg SIMPONI (golimumab injection) to healthy subjects produced a mean maximum serum concentration (Cmax) of approximately 2.5μ g/mL. SIMPONI (golimumab injection) exhibited dose-proportional pharmacokinetics (PK) in patients with active RA over the dose range of 0.1 to 10.0 mg/kg following a single intravenous (IV) dose. Following a single IV administration over the same dose range in patients with active RA, mean systemic clearance of SIMPONI (golimumab injection) was estimated to be 4.9 to 6.7 mL/day/kg, and mean volume of distribution ranged from 58 to 126 mL/kg. The volume of distribution for SIMPONI (golimumab injection) indicates that SIMPONI (golimumab injection) is distributed primarily in the circulatory system with limited extravascular distribution. Median terminal half-life values were estimated to be approximately 2 weeks in healthy subjects and patients with active RA, PsA or AS. By cross-study comparisons of mean AUCinf values following an IV or SC administration of SIMPONI (golimumab injection) , the absolute bioavailability of SC SIMPONI (golimumab injection) was estimated to be approximately 53%.

When 50 mg SIMPONI (golimumab injection) was administered SC to patients with RA, PsA or AS every 4 weeks, serum concentrations appeared to reach steady state by Week 12. With concomitant use of methotrexate (MTX), treatment with 50 mg SIMPONI (golimumab injection) SC every 4 weeks resulted in a mean steady-state trough serum concentration of approximately 0.4-0.6μg/mL in patients with active RA, approximately 0.5μg/mL in patients with active PsA, and approximately 0.8μg/mL in patients with active AS. Patients with RA, PsA and AS treated with SIMPONI (golimumab injection) 50 mg and MTX had approximately 52%, 36% and 21% higher mean steady-state trough concentrations of golimumab, respectively compared with those treated with SIMPONI (golimumab injection) 50 mg without MTX. The presence of MTX also decreased anti-golimumab antibody incidence from 7% to 2% [see ADVERSE REACTIONS]. For RA, SIMPONI (golimumab injection) should be used with MTX. In the PsA and AS trials, the presence or absence of concomitant MTX did not appear to influence clinical efficacy and safety parameters [see DRUG INTERACTIONS and Clinical Studies].

Population PK analyses indicated that concomitant use of NSAIDs, oral corticosteroids, or sulfasalazine did not influence the apparent clearance of SIMPONI (golimumab injection) .

Population PK analyses showed there was a trend toward higher apparent clearance of SIMPONI (golimumab injection) with increasing weight. However, across the PsA and AS populations, no meaningful differences in clinical efficacy were observed among the subgroups by weight quartile. The RA trial in MTX­experienced and TNF-blocker-naïvepatients (Study RA-2) did show evidence of a reduction in clinical efficacy with increasing body weight, but this effect was observed for both tested doses of SIMPONI (golimumab injection) (50 mg and 100 mg). Therefore, there is no need to adjust the dosage of SIMPONI (golimumab injection) based on a patient's weight.

Population PK analyses suggested no PK differences between male and female patients after body weight adjustment in the RA and PsA trials. In the AS trial, female patients showed 13% higher apparent clearance than male patients after body weight adjustment. Subgroup analysis based on gender showed that both female and male patients achieved clinically significant response at the proposed clinical dose. Dosage adjustment based on gender is not needed.

Population PK analyses indicated that PK parameters of SIMPONI (golimumab injection) were not influenced by age in adult patients. Patients with age 65 years had apparent clearance of SIMPONI (golimumab injection) similar to patients with age < 65 years. No ethnicity-related PK differences were observed between Caucasians and Asians, and there were too few patients of other races to assess for PK differences.

Patients who developed anti-SIMPONI (golimumab injection) antibodies generally had lower steady-state serum trough concentrations of SIMPONI (golimumab injection) .

No formal study of the effect of renal or hepatic impairment on the PK of golimumab was conducted.

Clinical Studies

Rheumatoid Arthritis

The efficacy and safety of SIMPONI (golimumab injection) were evaluated in 3 multicenter, randomized, double-blind, controlled trials (Studies RA-1, RA-2, and RA-3) in 1542 patients ≥ 18 years of age with moderately to severely active RA, diagnosed according to the American College of Rheumatology (ACR) criteria, for at least 3 months prior to administration of study agent. Patients were required to have at least 4 swollen and 4 tender joints. SIMPONI (golimumab injection) was administered subcutaneously at doses of 50 mg or 100 mg every 4 weeks. Double-blinded controlled efficacy data were collected and analyzed through Week 24. Patients were allowed to continue stable doses of concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs and patients may have received oral MTX during the trials.

Study RA-1 evaluated 461 patients who were previously treated (at least 8 to 12 weeks prior to administration of study agent) with one or more doses of a biologic TNF-blocker without a serious adverse reaction. Patients may have discontinued the biologic TNF-blocker for a variety of reasons. Patients were randomized to receive placebo (n = 155), SIMPONI (golimumab injection) 50 mg (n = 153), or SIMPONI (golimumab injection) 100 mg (n = 153). Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited.

Study RA-2 evaluated 444 patients who had active RA despite a stable dose of at least 15 mg/week of MTX and who had not been previously treated with a biologic TNF-blocker. Patients were randomized to receive background MTX (n = 133), SIMPONI (golimumab injection) 50 mg + background MTX (n = 89), SIMPONI (golimumab injection) 100 mg + background MTX (n = 89), or SIMPONI (golimumab injection) 100 mg monotherapy (n = 133). The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited.

Study RA-3 evaluated 637 patients with active RA who were MTX-naïve and had not previously been treated with a biologic TNF-blocker. Patients were randomized to receive MTX (n = 160), SIMPONI (golimumab injection) 50 mg + MTX (n = 159), SIMPONI (golimumab injection) 100 mg + MTX (n = 159), or SIMPONI (golimumab injection) 100 mg monotherapy (n = 159). For patients receiving MTX, MTX was administered at a dose of 10 mg/week beginning at Week 0 and increased to 20 mg/week by Week 8. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited.

The primary endpoint in Study RA-1 and Study RA-2 was the percentage of patients achieving an ACR 20 response at Week 14 and the primary endpoint in Study RA-3 was the percentage of patients achieving an ACR 50 response at Week 24.

In Studies RA-1, RA-2, and RA-3, the median duration of RA disease was 9.4, 5.7, and 1.2 years; and 99%, 75%, and 54% of the patients used at least one DMARD in the past, respectively. Approximately 77% and 57% of patients received concomitant NSAIDs and low dose corticosteroids, respectively, in the 3 pooled RA trials.

Clinical Response

In the 3 RA trials, a greater percentage of patients treated with the combination of SIMPONI (golimumab injection) and MTX achieved ACR responses at Week 14 (Studies RA-1 and RA-2) and Week 24 (Studies RA­1, RA-2, and RA-3) versus patients treated with the MTX alone. There was no clear evidence of improved ACR response with the higher SIMPONI (golimumab injection) dose group (100 mg) compared to the lower SIMPONI (golimumab injection) dose group (50 mg). In Studies RA-2 and RA-3, the SIMPONI (golimumab injection) monotherapy groups were not statistically different from the MTX monotherapy groups in ACR responses. Table 2 shows the proportion of patients with the ACR response for the SIMPONI (golimumab injection) 50 mg and control groups in Studies RA-1, RA-2, and RA-3. In the subset of patients who received SIMPONI (golimumab injection) in combination with MTX in Study RA-1, the proportion of patients achieving ACR 20, 50 and 70 responses at week 14 were 40%, 18%, and 13%, respectively, in the SIMPONI (golimumab injection) 50 mg + MTX group (N = 103) compared with 17%, 6%, and 2%, respectively, in the placebo + MTX group (N = 107). Table 3 shows the percent improvement in the components of the ACR response criteria for the SIMPONI (golimumab injection) 50 mg + MTX and MTX groups in Study RA-2. The percent of patients achieving ACR 20 responses by visit for Study RA-2 is shown in Figure 1. ACR 20 responses were observed in 38% of patients in the SIMPONI (golimumab injection) 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI (golimumab injection) administration.

Table 2: Studies RA-1, RA-2, and RA-3 Proportion of Patients with an ACR Response^a

Table 3: Study RA-2- Median Percent Improvement from Baseline in the Individual ACR Components at Weeks 14^a

Figure 1: Study RA - 2 – Percent of Patients Achieving ACR 20 Response by Visit: Randomized Patients*

Physical Function Response in Patients with RA

In Studies RA-1 and RA-2, the SIMPONI (golimumab injection) 50 mg groups demonstrated a greater improvement compared to the control groups in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24: 0.25 vs. 0.05 in RA-1, 0.47 vs. 0.13 in RA-2, respectively. Also in Studies RA-1 and RA-2, the SIMPONI (golimumab injection) 50 mg groups compared to the control groups had a greater proportion of HAQ responders (change from baseline > 0.22) at Week 24: 44% vs. 28%, 65% vs. 35%, respectively.

Psoriatic Arthritis

The safety and efficacy of SIMPONI (golimumab injection) were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 405 adult patients with moderately to severely active PsA ( ≥ 3 swollen joints and ≥ 3 tender joints) despite NSAID or DMARD therapy (Study PsA). Patients in this study had a diagnosis of PsA for at least 6 months with a qualifying psoriatic skin lesion of at least 2 cm in diameter. Previous treatment with a biologic TNF-blocker was not allowed. Patients were randomly assigned to placebo (n = 113), SIMPONI (golimumab injection) 50 mg (n = 146), or SIMPONI (golimumab injection) 100 mg (n = 146) given subcutaneously every 4 weeks. Patients were allowed to receive stable doses of concomitant MTX ( ≤ 25 mg/week), low dose oral corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited. The primary endpoint was the percentage of patients achieving ACR 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24.

Patients with each subtype of PsA were enrolled, including polyarticular arthritis with no rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal (DIP) joint arthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%). The median duration of PsA disease was 5.1 years, 78% of patients received at least one DMARD in the past, and approximately 48% of patients received MTX, and 16% received low dose oral steroids.

Clinical Response in Patients with PsA

SIMPONI (golimumab injection) ± resulted in significant improvement in signsMTX, compared with and symptoms as demonstrated by the proportion of patients with an ACR 20 response at Week 14 in Study PsA (see Table 4). There was no clear evidence of improved ACR response with the higher SIMPONI (golimumab injection) dose group (100 mg) compared to the lower SIMPONI (golimumab injection) dose group (50 mg). ACR responses observed in the SIMPONI (golimumab injection) -treated groups were similar in patients receiving and not receiving concomitant MTX. Similar ACR 20 responses at Week 14 were observed in patients with different PsA subtypes. However, the number of patients with arthritis mutilans was too small to allow meaningful assessment. SIMPONI (golimumab injection) 50 mg treatment also resulted in significantly greater improvement compared with placebo for each ACR component in Study PsA (Table 5). Treatment with SIMPONI (golimumab injection) resulted in improvement in enthesitis and skin manifestations in patients with PsA. However, the safety and efficacy of SIMPONI (golimumab injection) in the treatment of patients with plaque psoriasis has not been established.

The percent of patients achieving ACR 20 responses by visit for Study PsA is shown in Figure 2. ACR 20 responses were observed in 31% of patients in the SIMPONI (golimumab injection) 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI (golimumab injection) administration.

Table 4: Study PsA - Proportion of Patients with ACR Responses

Table 5: Study PsA - Percent Improvement in ACR Components at Week 14

Figure 2: Study PsA – Percent of ACR 20 PsA Responders by Visit: Randomized Patients*

Physical Function Response in Patients with PsA

In Study PsA, SIMPONI (golimumab injection) 50 mg demonstrated a greater improvement compared to placebo in the change in mean Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline to Week 24 (0.33 and -0.01, respectively). In addition, the SIMPONI (golimumab injection) 50 mg group compared to the placebo group had a greater proportion of HAQ responders ( ≥ 0.3 change from baseline) at Week 24: 43% vs. 22%, respectively.

Ankylosing Spondylitis

The safety and efficacy of SIMPONI (golimumab injection) were evaluated in a multi-center, randomized, double-blind, placebo-controlled trial in 356 adult patients with active ankylosing spondylitis according to modified New York criteria for at least 3 months (Study AS). Patients had symptoms of active disease [defined as a Bath AS Disease Activity Index (BASDAI) ≥ 4 and VAS for total back pain of ≥ 4, on scales of 0 to 10 cm] despite current or previous NSAID therapy. Patients were excluded if they were previously treated with a biologic TNF-blocker or if they had complete ankylosis of the spine. Patients were randomly assigned to placebo (n = 78), SIMPONI (golimumab injection) 50 mg (n = 138), or SIMPONI (golimumab injection) 100 mg (n = 140) administered subcutaneously every 4 weeks. Patients were allowed to continue stable doses of concomitant MTX, sulfasalazine (SSZ), hydroxychloroquine (HCQ), low dose corticosteroids (equivalent to < 10 mg of prednisone a day), and/or NSAIDs during the trial. The use of other DMARDs including cytotoxic agents or other biologics was prohibited.

The primary endpoint was the percentage of patients achieving an ASsessment in Ankylosing Spondylitis (ASAS) 20 response at Week 14. Placebo-controlled efficacy data were collected and analyzed through Week 24.

In Study AS, the median duration of AS disease was 5.6 years, median duration of inflammatory back pain was 12 years, 83% were HLA-B27 positive, 24% had prior joint surgery or procedure, and 55% received at least one DMARD in the past. During the trial, the use of concomitant DMARDs and/or NSAIDs was as follows: MTX (20%), SSZ (26%), HCQ (1%), low dose oral steroids (16%), and NSAIDs (90%).

Clinical Response in Patients with AS

In Study AS, SIMPONI (golimumab injection) ± DMARDs treatment, compared with placebo ± DMARDs, resulted in a significant improvement in signs and symptoms as demonstrated by the proportion of patients with an ASAS 20 response at Week 14 (see Table 6). There was no clear evidence of improved ASAS response with the higher SIMPONI (golimumab injection) dose group (100 mg) compared to the lower SIMPONI (golimumab injection) dose group (50 mg). Table 7 shows the percent improvement in the components of the ASAS response criteria for the SIMPONI (golimumab injection) 50 mg ± DMARDs and placebo ± DMARDs groups in Study AS.

The percent of patients achieving ASAS 20 responses by visit for Study AS is shown in Figure 3. ASAS 20 responses were observed in 48% of patients in the SIMPONI (golimumab injection) 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI (golimumab injection) administration.

Table 6: Study AS – Proportion of ASAS Responders at Weeks 14 and 24

Table 7: Study AS- Median Percent Improvement in ASAS Components at Week 14

Figure 3: Study AS – Percent of AS Patients Achieving ASAS 20 Response by Visit: Randomized Patients*

Last reviewed on RxList: 8/31/2010
This monograph has been modified to include the generic and brand name in many instances.