"The U.S. Food and Drug Administration today approved Inflectra (infliximab-dyyb) for multiple indications. Inflectra is administered by intravenous infusion. This is the second biosimilar approved by the FDA.
Inflectra is biosimilar to"...
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 rheumatoid arthritis. TNFα is an important mediator of the articular inflammation that is characteristic of RA. 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). The clinical relevance of these findings is unknown.
Following treatment with SIMPONI ARIA in patients with RA, decreases from baseline were observed in tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-3 (MMP-3), resistin, interleukin-6 (IL-6), macrophage inflammatory protein-1 (MIP-1b), vascular endothelial growth factor (VEGF), serum amyloid A (SAA), S100A12, and high sensitivity C-Reactive protein (hsCRP). Conversely, increases from baseline were observed in tartrate-resistant acid phosphatase (TRAP-5b). The clinical relevance of this information is not known.
Following a single intravenous administration of 2 mg/kg SIMPONI ARIA, a mean C max of 44.4 ± 11.3 μg/mL was observed in patients with RA. Data directly comparing 2 mg/kg intravenous administration and 50 mg subcutaneous administration are not available.
Following a single intravenous administration of 2 mg/kg SIMPONI ARIA, the mean volume of distribution was estimated to be 115 ± 19 mL/kg in healthy subjects, and 151 ± 61 mL/kg in patients with RA. The volume of distribution of golimumab may indicate that golimumab is distributed primarily in the circulatory system with limited extravascular distribution.
The elimination pathways for golimumab have not been characterized.
Following a single intravenous administration of 2 mg/kg SIMPONI ARIA, the systemic clearance of golimumab was estimated to be 6.9 ± 2.0 mL/day/kg in healthy subjects and 7.6 ± 2.0 mL/day/kg in patients with RA. The mean terminal half-life was estimated to be 12 ± 3 days in healthy subjects and the mean terminal half-life in RA patients was 14 ± 4 days.
When 2 mg/kg SIMPONI ARIA was administered intravenously to patients with RA at weeks 0, 4 and every 8 weeks thereafter, serum concentrations reached steady-state by Week 12. Following IV administration, concomitant administration of methotrexate decreases the clearance of SIMPONI ARIA by approximately 9% based on population PK analysis. In addition, concomitant administration of methotrexate decreases the SIMPONI ARIA clearance by reducing the development of anti-golimumab antibodies. With concomitant use of MTX, treatment with 2 mg/kg golimumab every 8 weeks resulted in a mean steady-state trough serum concentration of approximately 0.4 ± 0.4 μg/mL in patients with active RA despite MTX therapy.
Population PK analysis indicated that concomitant use of NSAIDs, oral corticosteroids, or sulfasalazine did not influence the apparent clearance of SIMPONI following SC administration.
Patients who developed anti-golimumab antibodies generally had low trough steady-state serum concentrations of golimumab.
No formal study of the effect of renal or hepatic impairment on the PK of golimumab was conducted.
Golimumab exhibited approximately dose-proportional pharmacokinetics in patients with RA over the dose range of 0.1 to 10.0 mg/kg following a single intravenous dose.
Effect of Weight on Pharmacokinetics
Following intravenous administration, patients with higher body weight tended to have higher serum golimumab concentrations than patients with lower body weights when golimumab was administered on a mg/kg (body weight) basis. However, based on population PK analysis, there were no clinically relevant differences in golimumab exposure following intravenous administration of 2 mg/kg SIMPONI ARIA in patients across a range of different body weights.
The efficacy and safety of SIMPONI ARIA were evaluated in one multicenter, randomized, double-blind, controlled trial (Trial 1) in 592 patients ≥ 18 years of age with moderately to severely active RA despite concurrent MTX therapy and had not previously been treated with a biologic TNF-blocker. Patients were diagnosed according to the American College of Rheumatology (ACR) criteria, at least 3 months prior to administration of study agent and were required to have at least 6 swollen and 6 tender joints. Patients were randomized to receive either SIMPONI ARIA 2 mg/kg (N=395) or placebo (N=197) over a 30-minute intravenous infusion at Weeks 0, 4 and every 8 weeks thereafter in addition to their weekly maintenance MTX dose (15-25 mg). All patients receiving placebo + MTX received SIMPONI ARIA + MTX after Week 24, but the trial remained blinded until all patients had completed 108 weeks of treatment. Efficacy data were collected and analyzed through Week 52. Patients were allowed to continue stable doses of concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs. The use of other DMARDs including cytotoxic agents or other biologics was prohibited.
The primary endpoint in Trial 1 was the percentage of patients achieving an ACR 20 response at Week 14. In Trial 1, the majority of subjects were women (82%) and were Caucasian (80%) with a median age of 52 years and a median weight of 70 kg. Median disease duration was 4.7 years, and 50% of the patients used at least one DMARD other than MTX in the past. At baseline, 81% of patients received concomitant NSAIDs and 81% of patients received low-dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day). The median baseline DAS28-CRP was 5.9 and the median van der Heijde-Sharp score at baseline was 28.5.
A greater percentage of patients treated with the combination of SIMPONI ARIA + MTX achieved ACR 20 at Week 14 and ACR 50 at Week 24 versus patients treated with the placebo + MTX as shown in Table 2. The percent of patients achieving ACR 20 responses by visit for Trial 1 is shown in Figure 1.
Table 2: Trial 1 – Proportion of Patients with an ACR
|Trial 1 Active RA, despite MTX|
|Placebo + MTX||SIMPONI ARIA + MTX||95% CIa|
|Week 14||25%||59%||25.9, 41.4|
|Week 24||32%||63%||23.3, 39.4|
|Week 14||9%||30%||15.3, 27.2|
|Week 24||13%||35%||15.1, 28.4|
|Week 14||3%||12%||5.3, 13.4|
|Week 24||4%||18%||8.8, 18.1|
|a For difference in proportions.
b N reflects randomized patients.
Figure 1: Trial 1 – Percent
of Patients Achieving ACR 20 Response Over Time: Randomized Patients
The improvement in all components of the ACR response criteria for the SIMPONI ARIA + MTX group was greater compared to the placebo + MTX group in Trial 1 as shown in Table 3.
Table 3: Trial 1 -
Components of ACR Response at Week 14
|Trial 1 Active RA, despite MTX|
|Placebo + MTX||SIMPONI ARIA + MTX|
|Number of swollen joints (0-66)|
|Number of tender joints (0-68)|
|Patient’s assessment of pain (0-10)|
|Patient’s global assessment of disease activity (0-10)|
|Physician’s global assessment of disease activity (0-10)|
|HAQ score (0-3)|
|CRP (mg/dL) (0-1)|
|Note: All values are means.
a N reflects randomized patients; actual number of patients evaluable for each endpoint may vary.
At Week 14, a greater proportion of patients treated with SIMPONI ARIA + MTX achieved a low level of disease activity as measured by a DAS28-CRP less than 2.6 compared with the placebo + MTX group (15% compared to 5%; 95% CI for difference [6.3%, 15.5%]).
In Trial 1, structural joint damage was assessed radiographically and expressed as a change in van der Heijde-Modified Sharp Score (vdH-S) and its components, the erosion score and Joint Space Narrowing (JSN) score, at Week 24 compared to baseline. The SIMPONI ARIA + MTX treatment group inhibited the progression of structural damage compared with placebo + MTX, as assessed by total vdH-S score as shown in Table 4.
Table 4: Trial 1 –
Radiographic Change From Baseline at Week 24
|Placebo + MTX
|SIMPONI ARIA + MTX
|Change Total vdH-S Score||1.1||0.03*|
|Change Erosion Score||0.5||-0.1|
|Change JSN Score||0.6||0.1|
|a N reflects randomized patients.
b p-value is displayed only for the major secondary endpoint.
* p ≤ 0.001.
At Week 24, a greater proportion of patients in the SIMPONI ARIA + MTX group (71%) had no progression of structural damage (change in the total vdH-S score ≤ 0), compared to 57% of patients in the placebo + MTX group. At Week 52, the mean change from baseline in total vdH-S score was 1.2 in patients originally randomized to placebo + MTX who crossed over to SIMPONI ARIA + MTX at Week 16 or Week 24, and 0.1 in patients originally randomized to SIMPONI ARIA + MTX who remained on active treatment.
Physical Function Response in Patients with RA
Physical function was assessed by the disability index of the Health Assessment Questionnaire (HAQ-DI). At Week 14, the SIMPONI ARIA + MTX group showed greater mean improvement in the HAQ-DI compared with placebo + MTX (0.5 compared to 0.2; 95% CI for difference [0.2, 0.4]).
Other Health-Related Outcomes
General health status was assessed by the 36-item Short Form Health Survey (SF-36). In Trial 1, patients receiving SIMPONI ARIA + MTX demonstrated greater improvement from baseline compared with placebo + MTX in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36.
Last reviewed on RxList: 3/3/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Simponi Aria Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Get the latest treatment options