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Pharmacodynamics: Nonclinical: The binding of human TNF by golimumab was shown to neutralize TNF-induced cell-surface expression of the adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 by human endothelial cells. TNF-induced secretion of interleukin (IL)-6, IL-8 and granulocyte-macrophage colony stimulating factor (GM-CSF) by human endothelial cells was also inhibited by golimumab. Consistent with other human IgG1 antibodies, golimumab is capable of binding to Fc receptors and activating complement.
However, no golimumab-mediated cell lysis was seen with lipopolysaccharide (LPS)-stimulated human monocytes upon addition of complement or effector cells. In addition, no golimumab-induced apoptosis was detected with LPS-stimulated human peripheral blood mononuclear cells. The effect of golimumab in vivo was tested in a human TNF transgenic mouse model of experimental arthritis. Golimumab treatment produced a statistically significant delay in the onset of clinical symptoms compared with untreated mice, as well as a significant reduction in joint pathology.
Clinical: SIMPONI was effective in modulating select markers of inflammation and bone metabolism across indications. Improvement in C-reactive protein (CRP) levels were observed relative to placebo groups and treatment with SIMPONI resulted in significant reductions from baseline in serum levels of IL-6, ICAM-1, matrix metalloproteinase-3 (MMP-3) and vascular endothelial growth factor (VEGF) compared to control treatment. In addition, levels of TNFα were significantly reduced in RA and AS patients and levels of IL-8 were reduced in PsA patients.
These changes were observed at the first assessment (Week 4) after the initial SIMPONI administration and were generally sustained through Weeks 14 and/or 24. SIMPONI with or without methotrexate (MTX) resulted in significant changes in serum levels of select markers of bone metabolism [increases in osteocalcin and procollagen type I N-terminal propeptide (PINP) and decreases in deoxy-pyridinoline (DPD) levels] at Week 4. All of these biomarker changes are consistent with an improvement in the disease processes with reduced inflammation, increased bone growth and decreased bone resorption.
Clinical Trials: Rheumatoid Arthritis: Study demographics and trial design: The efficacy and safety of SIMPONI were evaluated in three multicentre, randomized, double-blind, placebo-controlled studies in over 1,500 patients ≥18 years of age with moderately to severely active RA diagnosed according to American College of Rheumatology (ACR) criteria for at least 3 months prior to screening (Table 2). Patients had at least 4 swollen and 4 tender joints. SIMPONI was administered subcutaneously at doses of 50 mg or 100 mg, with or without MTX, every 4 weeks. (See Table 2.)
Click on icon to see table/diagram/imageRA Study 1 (GO-FORWARD): Active Rheumatoid Arthritis Despite MTX: Study RA-1 (GO-FORWARD) 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 an anti-TNF agent. Patients were randomized to receive placebo + MTX (n=133), SIMPONI 50 mg + MTX (n=89), SIMPONI 100 mg + MTX (n=89) or SIMPONI 100 mg monotherapy + placebo (n=133). The co-primary endpoints were the percent of patients achieving ACR 20 response at Week 14 and improvement from baseline in HAQ at Week 24. Major secondary endpoints included change from baseline in van der Heijde-modified Sharp (vdH-S) score at Week 24, DAS28 (using CRP) response at Week 14, ACR 20 response at Week 24, and improvement from baseline in HAQ at Week 14. All patients receiving placebo + MTX received SIMPONI 50 mg + MTX after Week 24, but the trial remained blinded until all patients had completed 52 weeks of treatment. At Week 52, patients entered the long-term extension phase and patients receiving SIMPONI 50 mg could have the dose increased to 100 mg at the discretion of the investigator. Through Week 252, the time point for the last scheduled study agent administration, 131 (29.5%) treated subjects discontinued study agent. Efficacy data were collected and analyzed through Week 256. Through Week 252, the time point for the last scheduled study agent administration, 29 (32.6%) treated subjects initially randomized to receive golimumab 50 mg, continually received the authorized dose of golimumab 50 mg once a month.
RA Study 2 (GO-AFTER): Active Rheumatoid Arthritis, previously treated with anti-TNFα agent(s): Study RA-2 (GO-AFTER) evaluated 445 patients who were previously treated with one or more of the anti-TNF agents adalimumab, etanercept, or infliximab, without serious adverse reaction. Reasons for discontinuation of prior anti-TNF therapies included lack of efficacy (59%), intolerance (17%), and/or reasons other than safety or efficacy (39%). Patients were randomized to receive placebo (n=150), SIMPONI 50 mg (n=147), and SIMPONI 100 mg (n=148). Patients were allowed to continue concomitant DMARD therapy with MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the study. The use of other DMARDs including cytotoxic agents or other biologics was prohibited. The primary endpoint was the percent of patients achieving ACR 20 response at Week 14. Major secondary endpoints included ACR 50 response at Week 14, DAS28 (using CRP) response at Week 14, ACR 20 response at Week 24 and improvement from baseline in HAQ score at Week 24. Through Week 252, the time point for the last scheduled study agent administration, 276 (60.1%) treated subjects discontinued study agent. Efficacy data were collected and analyzed through Week 256. Through Week 252, the time point for the last scheduled study agent administration, 21 (14.3%) treated subjects initially randomized to receive golimumab 50 mg continually received the authorized dose of golimumab 50 mg once a month.
RA Study 3 (GO-BEFORE): Active Rheumatoid Arthritis, MTX Naïve: Study RA-3 (GO-BEFORE) evaluated 637 patients with active RA who were MTX-naïve and had not previously been treated with an anti-TNF agent. Patients were randomized to receive placebo + MTX (n=160), SIMPONI 50 mg + MTX (n=159), SIMPONI 100 mg + MTX (n=159) or SIMPONI 100 mg monotherapy + placebo (n=159). For patients receiving active 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 co-primary endpoints were the percent of patients achieving ACR 50 response at Week 24, and the change from baseline in vdH-S score at Week 52. Major secondary endpoints included the change from baseline in HAQ at Week 52, ACR 20 response at Week 24, the change from baseline in vdH-S score at Week 52 in subjects with abnormal CRP at baseline, and the percent of patients with abnormal CRP at baseline achieving an ACR 50 response at Week 24. At Week 52, patients entered the long-term extension phase in which patients receiving placebo + MTX who had at least 1 tender or swollen joint were switched to SIMPONI 50 mg + MTX. Patients receiving SIMPONI 50 mg could have the dose increased to 100 mg at the discretion of the investigator. Through Week 252, the time point for the last scheduled study agent administration, 215 (33.9%) treated subjects discontinued study agent.
Efficacy data were collected and analyzed through Week 256. Through Week 252, 62 (39%) treated subjects initially randomized to receive golimumab 50 mg, continually received the authorized dose of golimumab 50 mg once a month.
Study results: Reduction in Signs and Symptoms: In general, no clinically meaningful differences across efficacy measures were apparent between the SIMPONI 50 mg and 100 mg dosing regimens in each of the Phase 3 RA studies. Patients in the long-term extension may have their dose modified at the discretion of the study physician.
RA Study 1 (GO-FORWARD): Treatment with SIMPONI in patients with active RA despite MTX resulted in improvement in signs and symptoms as demonstrated by the percent of patients achieving an ACR 20 response at Week 14. A significantly greater percent of patients achieved an ACR 20 response in the SIMPONI 50 mg + MTX group than in the placebo + MTX group (p≤0.001) at Weeks 14 and 24. The percent of patients achieving ACR 50 and ACR 70 responses was also greater in the SIMPONI 50 mg + MTX group than in the placebo + MTX group at Weeks 14 and 24 (Table 3). (See Table 3.)
When ACR 20 responses over time were considered, improvement was observed at the first assessment (Week 4) after the first SIMPONI 50 mg + MTX administration, and was maintained through Week 24 (Figure 1). (See Figure 1.)
Click on icon to see table/diagram/imageThe percentages of patients achieving a DAS28 response were 72% and 73% for patients treated with SIMPONI 50 mg + MTX at Week 14 and at Week 24, respectively, compared to 50% and 42% in those who received placebo + MTX. Remission (defined as DAS28 <2.6) was achieved by 27% of patients treated with SIMPONI 50 mg + MTX and 7% of those who received placebo + MTX at Week 24.
Click on icon to see table/diagram/imageAmong 89 patients randomized to SIMPONI 50 mg + MTX, 70 patients were still on SIMPONI 50 mg + MTX treatment at Week 52. Among those, 64 (91%) and 43 (61%) out of 70 patients achieved DAS28 response and DAS28 remission, respectively. Forty-eight patients were still on SIMPONI 50 mg + MTX treatment at Week 104. Among those, 40 (83%), 33 (69%) and 24 (50%) out of 48 patients achieved ACR 20, 50 and 70 responses, respectively.
During the long-term extension study, of those patients initially randomized to receive SIMPONI 50 mg, 29 patients received only SIMPONI 50 mg + MTX treatment through Week 252. Among those, 26 (89.7%) showed an ACR 20 response at the last efficacy assessment (Week 256).
SIMPONI 50 mg + MTX treatment also resulted in significantly greater improvement for each ACR component compared with treatment with placebo + MTX (Table 4). (See Table 4.)
Click on icon to see table/diagram/imageRA Study 2 (GO-AFTER): Treatment with SIMPONI 50 mg in patients with active RA, previously treated with anti-TNF agent(s), resulted in significant improvement in signs and symptoms as demonstrated by ACR 20, 50 and 70 responses at Week 14 and 24 (Table 5).
When ACR 20 responses over time were considered, improvement was observed at the first assessment (Week 4) after the first SIMPONI 50 mg + DMARDs (MTX, SSZ and/or HCQ) administration, and was maintained through Week 24. (See Table 5.)
Click on icon to see table/diagram/imageDuring the long-term extension study, of those patients initially randomized to receive SIMPONI 50 mg, 21 patients had received only SIMPONI 50 mg treatment through Week 252. Among those, 12 (57.1%) had an ACR 20 response at the last efficacy assessment (Week 256).
Table 6 shows the percent of patients achieving an ACR 20 response by reported reason for discontinuation of one or more prior anti-TNF therapies. (See Table 6.)
Click on icon to see table/diagram/imageSIMPONI 50 mg treatment also resulted in significantly greater improvement for each ACR component compared with treatment with placebo. Swollen joint count for the SIMPONI 50 mg and placebo group improved by 44% and 20%, respectively at Week 14 and 33% and 1%, respectively at Week 24. Improvement in tender joint count was 34% compared with 6% at Week 14, and 29% compared with -7% at Week 24, for the SIMPONI 50 mg and placebo groups, respectively. Patients' and physicians' assessments and HAQ score were also significantly improved for SIMPONI 50 mg compared with placebo at Week 14 and 24. For SIMPONI 50 mg, there was a 37% improvement in CRP compared with 0% improvement for placebo at Week 14, and 15% compared with 0% at Week 24.
The percent of patients achieving a DAS28 (using CRP) response was significantly greater for those patients treated with SIMPONI 50 mg compared with those who received placebo at Week 14 (56% compared with 27%; p<0.001) and at Week 24 (45% compared with 21%; p<0.001).
RA Study 3 (GO-BEFORE): This study evaluated patients with active RA who were MTX naïve and had not previously been treated with an anti-TNF agent. The co-primary endpoint was the percent of patients achieving an ACR 50 response at Week 24. The percent of randomized patients achieving an ACR 50 response with SIMPONI + MTX compared to MTX plus placebo was not statistically significant (38.4 vs. 29.4%, p=0.053). The percentage of patients achieving an ACR 20 response at Week 24 (major secondary endpoint) was 62% for the SIMPONI 50 mg + MTX group compared with 49% for the placebo + MTX group.
At Week 52, 60% and 42% of patients who received SIMPONI 50 mg + MTX achieved ACR 20 and 50 responses, respectively, compared to 52% and 36% of patients who received MTX alone.
At Week 52, 15% of patients in the SIMPONI 50 mg + MTX group achieved a major clinical response, defined as maintenance of an ACR 70 response over a continuous 6-month period, compared with 7% of patients in the placebo + MTX group.
During the long-term extension study, of those patients initially randomized to receive SIMPONI 50 mg, 62 patients had received only SIMPONI 50 mg + MTX treatment through Week 252. Among those, 45 (72.6%) had an ACR 50 response at the last efficacy assessment (Week 256).
Radiographic Response: RA Study 3 (GO-BEFORE): In study GO-BEFORE, the change from baseline in the vdH-S score (a composite score of structural damage that radiographically measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet) was used to assess the degree of structural damage. Key radiographic results for the SIMPONI 50 mg dose group at Week 52 are presented in Table 7. (See Table 7.)
Click on icon to see table/diagram/imageAt Week 52, 74% of patients in the SIMPONI 50 mg + MTX group had no progression of structural damage as defined by a change from baseline in total vdH-S Score ≤0, compared to 58% in those with MTX plus placebo.
Improvement in Physical Function and Health-Related Quality of Life: RA Study 1 (GO-FORWARD): Patients treated with SIMPONI 50 mg showed significantly greater (p<0.001) improvement in the Disability Index of the Health Assessment Questionnaire (HAQ) score compared with placebo at Week 14 (mean ± SD 0.42 ± 0.50 vs. 0.16 ± 0.49) and Week 24 (mean ± SD 0.47 ± 0.55 vs. 0.13 ± 0.58). Among 89 subjects randomized to SIMPONI 50 mg + MTX, 48 were still on this treatment at Week 104. The mean (± SD) improvement in HAQ score from baseline was 0.67 ± 0.64 in patients receiving SIMPONI 50 mg + MTX. At Week 24, 47 (53.4%) patients treated with SIMPONI 50 mg + MTX had an improvement in HAQ of ≥0.3 units, compared to 43 (33.9%) of patients treated with placebo + MTX. At Week 104, 40 out of 47 (85%) SIMPONI 50 mg + MTX-treated patients maintained ≥0.3 units improvement in HAQ.
Patients treated with SIMPONI 50 mg showed significantly greater improvement (p<0.001) from baseline in SF-36 physical component summary (PCS) score compared to placebo at Week 14 (mean change ± SD 8.0 ± 7.2 vs. 2.4 ± 7.8, respectively) and at Week 24 (mean change ± SD 8.3 ± 8.3 vs. 2.5 ± 8.1). At Week 104, the mean (± SD) improvement in SF-36 PCS score from baseline was 11.0 ± 9.7 in patients treated with SIMPONI 50 mg + MTX (n=48).
Patients treated with SIMPONI 50 mg showed significantly greater improvement (p<0.001) from baseline in the FACIT-F scores compared to placebo at Week 14 (mean ± SD 7.58 ± 8.93 vs. 2.27 ± 9.24) and at Week 24 (mean ± SD 7.30 ± 8.65 vs. 2.16 ± 9.53).
RA Study 2 (GO-AFTER): The mean change from baseline in HAQ score at Week 24 was 0.23 ± 0.50 for the SIMPONI 50 mg group compared with 0.03 ± 0.50 for the placebo group (p<0.001).
The mean (± SD) change from baseline for the FACIT-F score at Week 14 was 6.02 ± 10.14 for the SIMPONI 50 mg group compared with 2.16 ± 9.74 for the placebo group (p=0.001).
Psoriatic Arthritis: Study Demographics and Trial Design: The safety and efficacy of SIMPONI were evaluated in a single PsA study (GO-REVEAL), a multicentre, randomized, double-blind, placebo-controlled (through Week 24) study assessing treatment with SIMPONI 50 mg or 100 mg administered as subcutaneous (SC) injections every 4 weeks in 405 adult patients with active PsA (Table 8). All patients randomized to placebo received SIMPONI 50 mg after Week 24, but the trial remained double-blind until all patients had completed 52 weeks of treatment. At Week 52, patients entered the long-term extension phase. Patients receiving SIMPONI 50 mg could have their dose increased to 100 mg at the discretion of the investigator. In addition, concomitant therapy with DMARDs (including MTX), corticosteroids, and NSAIDs could be added at the discretion of the investigator. Patients enrolled in this study were men and women with a diagnosis of PsA for at least 6 months with a psoriatic skin lesion of at least 2 cm in diameter and active disease with at least 3 swollen and 3 tender joints despite disease-modifying antirheumatic (DMARD) or nonsteroidal anti-inflammatory (NSAID) therapy. Patients with each subtype of psoriatic arthritis 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%).
Patients were randomly assigned to placebo (n=113), SIMPONI 50 mg (n=146), and SIMPONI 100 mg (n=146). The co-primary endpoints were percent of patients achieving ACR 20 response at Week 14 and change from baseline in total PsA modified vdH-S score at Week 24. Major secondary endpoints included percent of patients achieving ACR 20 response at Week 24, Psoriasis Area Severity Index (PASI) 75 response at Week 14 in a subset of patients with ≥3% Body Surface Area (BSA) psoriasis skin involvement at baseline, improvement from baseline in HAQ scores at Week 24, and change from baseline in the PCS score of the SF-36 at Week 14. Through Week 252, the time point for the last scheduled study agent administration, 126 (31.1%) randomized subjects discontinued study agent. Efficacy data were collected and analyzed through Week 256. Through Week 252, the time point for the last scheduled study agent administration, 43 (29.4%) treated subjects initially randomized to receive golimumab 50 mg, continually received the authorized dose of golimumab 50 mg once a month. (See Table 8.)
Click on icon to see table/diagram/imageStudy results: Reduction in Signs and Symptoms: No clinically meaningful differences across efficacy measures were apparent between the SIMPONI 50 mg and 100 mg dosing regimens in the Phase 3 PsA study. By study design, patients in the long-term extension may have their dose modified at the discretion of the study physician.
Treatment with SIMPONI 50 mg resulted in significant improvement in signs and symptoms as demonstrated by percent of patients achieving ACR 20 response at Week 14 (p<0.001). Responses observed in the SIMPONI-treated groups were similar in patients receiving and not receiving concomitant MTX (Table 9). (See Table 9.)
Click on icon to see table/diagram/imageACR 20 improvement was observed at the first assessment (Week 4) after the first SIMPONI administration, and was maintained through Week 24 (Figure 2). (See Figure 2.)
Click on icon to see table/diagram/imageThe percent of patients achieving an ACR 50 response at Week 14 was 30% and 2%, and at Week 24 was 32% and 4% for the SIMPONI 50 mg and placebo groups, respectively (p<0.001). The percent of patients achieving an ACR 70 response was 12% and 1% at Week 14, and at Week 24 was 19% and 1% for the SIMPONI 50 mg and placebo groups, respectively (p<0.001). Of the 146 subjects randomized to SIMPONI 50 mg, 70 patients remained on this dose at Week 104. Of these 70 patients, 64 (91.4%), 46 (65.7%) and 31 (44.3%) patients achieved ACR 20, 50 and 70 responses, respectively. Of the 146 subjects randomized to SIMPONI 50 mg, 43 patients remained on the SIMPONI 50 mg dose through Week 252. Of these, 37 (86%) patients had an ACR 20 response at the last efficacy assessment (Week 256).
Responses observed in the SIMPONI 50 mg group were similar in patients receiving and not receiving concomitant MTX.
The percent of patients achieving Psoriatic Arthritis Response Criteria (PsARC) and DAS28 response (using CRP) was also significantly greater in the SIMPONI 50 mg group compared with placebo at Week 14 and 24 (p<0.001).
SIMPONI treatment also resulted in significantly greater improvement compared with placebo for each ACR component (p<0.001, Table 10). (See Table 10.)
Click on icon to see table/diagram/imageAt Week 14 in patients with enthesitis at baseline, there was a significantly greater improvement from baseline in enthesitis score as measured by PsA-modified Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) with SIMPONI 50 mg compared with placebo (median 50% vs. 0%; p<0.001). Significant improvement was maintained through Week 24.
In patients with dactylitis at baseline, the improvement in dactylitis score was numerically greater in the SIMPONI 50 mg treatment group than in the placebo treatment group at both Week 14 and at Week 24 (median 76% vs. 0%, p=0.10; 100% vs. 42%, p=0.09 respectively).
Psoriasis Skin and Nail Response: Among patients with ≥3% BSA psoriasis skin involvement at baseline, a significantly greater percent of patients achieved PASI 75 response at Week 14 when treated with SIMPONI 50 mg compared with placebo. The percent of patients achieving a PASI 50 and 90 response in the SIMPONI 50 mg group at Week 14 was also greater than in placebo group (Table 11). The responses were maintained or increased through Week 24. Of the 109 subjects randomized to golimumab 50 mg and with ≥3% BSA psoriasis skin involvement at baseline, 48 patients were still on this treatment at Week 104. Of 48 patients, 33 (68.8%) achieved PASI 75 response at Week 104. (See Table 11.)
Click on icon to see table/diagram/imageNail physician global assessment (PGA) and Nail Psoriasis Severity Index (NAPSI) analyses were performed on patients with fingernail involvement at baseline. Percent change from baseline in NAPSI and improvement in nail PGA were significantly greater in patients treated with SIMPONI 50 mg as compared with placebo at both Week 14 and at Week 24 (p≤0.015).
Radiographic Response: Structural damage in both hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified for PsA by addition of hand distal interphalangeal (DIP) joints. Key radiographic results for the SIMPONI 50 mg dose at Week 24 are presented in Table 12. (See Table 12.)
Click on icon to see table/diagram/imageThe number of patients in the individual PsA subtypes was too small to derive meaningful conclusions on the effect of SIMPONI in each of the PsA subtypes.
At Week 24, 81% (118/146) of patients in the SIMPONI 50 mg group had no progression of structural damage (as defined by a change from baseline in total vdH-S Score ≤0), compared to 66% in those receiving placebo. Of the 146 patients initially randomized to SIMPONI 50 mg, X-ray data were available for 101 and 66 patients who remained on this treatment at Weeks 52 and 104, respectively. Of these patients, 77% (78/101) and 76% (50/66) of patients showed no progression from baseline at Week 52 and Week 104, respectively.
Improvement in Physical Function and Health-Related Quality of Life: In the PsA Study, patients treated with SIMPONI 50 mg showed significantly greater (p<0.001) improvement in the HAQ score compared with placebo at Week 14 (mean ± SD 0.31 ± 0.50 vs. 0.04 ± 0.44) and Week 24 (mean ± SD 0.33 ± 0.55 vs. -0.01 ± 0.49).
At Week 24, the percent of patients who achieved clinically meaningful improvements in HAQ of ≥0.30 change from baseline was also significantly greater in those patients receiving SIMPONI 50 mg when compared with placebo (p<0.001). At Week 104, 69 of the 146 (47.3%) patients randomized to SIMPONI 50 mg were still on this dose. The mean (± SD) improvement in HAQ score from baseline in these 69 patients was 0.54 ± 0.55.
In the PsA study, patients treated with SIMPONI 50 mg showed significantly greater improvement (p<0.001) from baseline in the SF-36 physical component summary (PCS) score compared to placebo at Week 14 (mean change ± SD 6.5 ± 8.9 vs. 0.6 ± 7.7) and at Week 24 (mean change ± SD 7.4 ± 9.2 vs. 0.7 ± 8.7).
Patients treated with SIMPONI 50 mg showed significantly greater improvement from baseline (p<0.05) in SF-36 mental component summary (MCS) score compared to placebo at Week 14 (mean ± SD 2.8 ± 10.3 vs. 0.4 ± 11.4) and Week 24 (mean ± SD 3.4 ± 10.5 vs. -0.6 ± 12.1).
Ankylosing Spondylitis: Study Demographics and Trial Design: The safety and efficacy of SIMPONI were evaluated in an AS Study (GO-RAISE), a multicentre, randomized, double-blind, placebo-controlled (through Week 24) study assessing treatment with SIMPONI 50 mg or 100 mg administered as subcutaneous (SC) injections every 4 weeks in 356 adult patients with active AS (Table 13). Patients enrolled in this study were men and women who had symptoms of active disease (defined as a BASDAI ≥4 and a VAS for total back pain of ≥4, each on a scale of 0 to 10 cm) despite current or previous disease modifying antirheumatic drug (DMARD) or nonsteroidal anti-inflammatory drug (NSAID) therapy. Patients with complete ankylosis of the cervical and lumbar spine were excluded from study participation. Through Week 252, the time point for the last scheduled study agent administration, 101 (28.5%) randomized subjects discontinued study agent. Efficacy data were collected and analyzed through Week 256. Through Week 252, the time point for the last scheduled study agent administration, 68 (49.3%) treated subjects initially randomized to receive golimumab 50 mg, continually received the authorized dose of golimumab 50 mg once a month.
Patients were randomly assigned to placebo (n=78), SIMPONI 50 mg (n=138) and SIMPONI 100 mg (n=140). Placebo-controlled efficacy data were collected and analyzed through Week 24. The primary endpoint was Assessment in Ankylosing Spondylitis 20 (ASAS 20) response at Week 14. Major secondary endpoints included ASAS 20 response at Week 24, Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14, and Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 14. (See Table 13.)
Click on icon to see table/diagram/imageStudy results: Reduction in signs and symptoms: In general, no clinically meaningful differences across efficacy measures were apparent between the SIMPONI 50 mg and 100 mg dosing regimens in the Phase 3 AS study. During the long-term extension patients may have their dose modified at the discretion of the study physician.
At Week 14, ASAS 20/40 responses were achieved by 59% and 45% respectively, of patients receiving SIMPONI 50 mg compared with 22% and 15% respectively of patients receiving placebo (p<0.001, Table 14). Improvement in signs and symptoms as measured by ASAS 20 was observed at the first assessment (Week 4) after the first SIMPONI administration, and was maintained through Week 24 (Figure 3).
Among 68 patients who remained on the SIMPONI 50 mg dose through Week 252, 59 (86.8%) patients had an ASAS 20 response at the last efficacy assessment (Week 256). (See Figure 3 and Table 14.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imagePatients treated with SIMPONI 50 mg achieved significantly greater improvements in all ASAS 20 components compared with placebo (Table 15). (See Table 15.)
Click on icon to see table/diagram/imageAdditional measures of efficacy such as ASAS partial remission, ASAS 5/6 response, and BASDAI 50, 70, and 90 were statistically significant at Weeks 14 and 24 for SIMPONI 50 mg compared with placebo (p<0.001).
Improvement in Physical Function: Median improvement in the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14 was 1.4 in the SIMPONI 50 mg group, compared with worsening by 0.1 in the placebo group (p<0.001). The improvement in physical function was maintained at Week 24 in SIMPONI-treated patients.
Improvement in Range of Motion: No significant change in BASMI was observed at Weeks 14 or 24 in the SIMPONI 50 mg group compared with the placebo group. However, in the 50 mg SIMPONI group vs. placebo, significant median improvements from baseline were observed at Weeks 14 and 24 for lumbar flexion, lumbar side flexion at Week 24, and intermalleolar distance measurements at both Weeks 14 and Week 24 (p<0.05).
Improvement in Health-Related Quality of Life: In the AS study, patients treated with SIMPONI 50 mg showed significantly greater improvement from baseline (p<0.001) in SF-36 physical component summary (PCS) score compared to placebo at Week 14 (mean change ± SD 8.8 ± 9.6 vs. 3.0 ± 7.2) and was maintained through Week 24.
Improvement in Sleep: Patients treated with SIMPONI 50 mg showed significantly greater median improvement from baseline in sleep scores, as measured by the 20-point Jenkins Sleep Evaluation Questionnaire, compared with placebo at Week 14 (-3.0 vs. 0.0; p<0.001) and Week 24 (-3.0 vs. -1.0; p<0.001).
Non-radiographic Axial Spondyloarthritis: Study demographics and trial design: The safety and efficacy of SIMPONI 50 mg administered subcutaneously every 4 weeks were evaluated in a multi-center, randomized, double-blind, placebo-controlled (through Week 16) study (GO-AHEAD) in adult patients with severe active nr-Ax SpA (defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but that did not meet the modified New York criteria for AS). Subjects had a diagnosis of active Axial SpA of ≤5 years duration, and chronic back pain of ≥3 month duration. All eligible subjects were to be randomized in a 1:1 ratio to either the golimumab 50 mg treatment arm (N = 98) or the placebo treatment arm (N = 100). Subjects were stratified based on CRP level (limited to ≤60% of patients with CRP levels below the upper limit of normal at baseline) and evidence of sacroiliitis (active inflammation) on MRI (limited to ≤50% of patients with no MRI evidence of sacroiliitis at baseline). Subjects who successfully completed Part 1 (Weeks 0-16), were eligible to participate in Part 2 (Weeks 16-48) of the trial in which all patients received SIMPONI 50 mg administered subcutaneously every 4 weeks through Week 48. Efficacy assessments were performed through Week 52 and safety follow-up through Week 60. Approximately 93% (176/189) of patients who were receiving SIMPONI at the beginning of the open-label extension (Week 16) remained on treatment through the end of the study (Week 52).
Patients enrolled in this study had active disease, defined as a BASDAI ≥4 cm and a VAS for total back pain of ≥4 cm, each on a scale of 0 to 10 cm, and either experienced an inadequate response to NSAID therapy or were intolerant to NSAID therapy.
Patients who previously received TNF-α blockers or any biological agents were excluded from the study.
The primary endpoint was ASAS 20 response at Week 16. Major secondary endpoints included ASAS 40 response at Week 16, BASDAI 50 response at Week 16, ASAS partial remission at Week 16, and the change in the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI sacroiliac joints score from baseline to Week 16.
Baseline demographics and disease characteristics were generally comparable across both treatment groups. At baseline, the majority of patients (67%) had a diagnosis of nr-Ax SpA of less than 1 year duration. The mean BASDAI score at baseline was 6.5±1.5 cm. Approximately 81% of the total patient population at baseline received concomitant NSAID therapy. Approximately 41% of patients showed elevated CRP levels > upper limit of normal, 67% of subjects had evidence of sacroiliitis on MRI, and 80% showed evidence of elevated CRP levels > upper limit of normal and/or evidence of sacroiliitis on MRI. Most patients were male (57%), all (100%) were Caucasian, and the mean age was 31.2 (±7.2) years.
Analyses were performed on the All Treated population (AT, N=197). A subpopulation defined by elevated CRP above the upper limit of normal and/or evidence of sacroiliitis on MRI at baseline (n=158/197, 80.2%) was also evaluated.
Reduction in signs and symptoms: Treatment with SIMPONI 50 mg resulted in improvement in signs and symptoms as demonstrated by the proportion of subjects with an ASAS 20 response at Week 16 (Table 16). Figure 4 shows the proportion of subjects achieving ASAS 20 responses by visit. (See Figure 4 and Table 16.)
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Click on icon to see table/diagram/imageThe proportion of subjects achieving BASDAI 50 response at Week 16 in the golimumab 50 mg group (57.7%) was significantly greater (p<0.0001) than in the placebo group (30.0%).
The proportion of subjects achieving ASAS partial remission at Week 16 in the golimumab 50 mg group (33.0%) was significantly greater (p=0.0136) than in the placebo group (18.0%).
In the subpopulation of patients with elevated CRP (> the upper limit of normal) and/or evidence of sacroiliitis on MRI at baseline, comparable results to the AT population were observed in ASAS 20, ASAS 40, BASDAI 50 and ASAS partial remission.
Among subjects treated with golimumab 50 mg who remained on treatment through the end of the study (Week 52), improvements in ASAS 20, ASAS 40, BASDAI 50, and ASAS partial remission were comparable to those reported at Week 16.
Table 17 shows the percent improvement in the components of the ASAS response criteria for the SIMPONI 50 mg and placebo groups at Week 16. (See Table 17.)
Click on icon to see table/diagram/imageSpinal mobility was assessed by BASMI. The mean change from baseline in BASMI score at Week 16 in the golimumab 50 mg-treated group was -0.5 cm vs. -0.1 cm in the placebo-treated group.
The mean change from baseline in CRP at Week 16 was -0.99 mg/dL in the golimumab 50 mg group and was -0.35 mg/dL in the placebo group.
The mean change from baseline in the SPARCC (Spondyloarthritis Research Consortium of Canada) MRI SI joints score was -5.3 in the golimumab 50 mg group and was -0.9 in the placebo group at Week 16.
The change from baseline in the ASQoL score at Week 16 was -5.2 in the golimumab 50 mg group and -1.8 in the placebo group.
Ulcerative Colitis: Study demographics and trial design: The safety and efficacy of SIMPONI were evaluated in two multi-center, randomized, double-blind, placebo-controlled Phase 3 clinical studies in patients ≥18 years of age. (See Table 18.)
Click on icon to see table/diagram/imageUC Study 1 (PURSUIT-Induction): UC Study 1 was an induction study conducted in patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12; Endoscopy subscore ≥2) who had an inadequate response to or had failed to tolerate conventional therapies, or were corticosteroid dependent. The study was a combination Phase 2 (dose finding) and Phase 3 (dose confirming) study. In the dose finding portion of the study, patients were randomized to one of 4 treatment groups: 400 mg SIMPONI SC at Week 0 and 200 mg at Week 2 (400/200 mg), 200 mg SIMPONI SC at Week 0 and 100 mg at Week 2 (200/100 mg), 100 mg SIMPONI SC at Week 0 and 50 mg at Week 2 (100/50 mg), or placebo SC at Weeks 0 and 2. In the dose confirming portion of the study, efficacy was evaluated in 761 patients who were randomized to receive either 400 mg SIMPONI SC at Week 0 and 200 mg at Week 2, 200 mg SIMPONI SC at Week 0 and 100 mg at Week 2, or placebo SC at Weeks 0 and 2. Concomitant stable doses of oral aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted.
UC Study 2 (PURSUIT-Maintenance): UC Study 2 was a maintenance study that evaluated 456 patients who achieved clinical response with SIMPONI induction. Patients were randomized to receive SIMPONI 50 mg, SIMPONI 100 mg or placebo administered subcutaneously every 4 weeks. Concomitant stable doses of oral aminosalicylates and/or immunomodulatory agents were permitted. Corticosteroids were to be tapered at the start of the maintenance study. The efficacy of SIMPONI through Week 54 was assessed in this study. Patients who completed the maintenance study through Week 54 continued treatment through Week 216. Efficacy assessments were performed through the extension study.
Clinical Endpoints: The primary endpoint for UC Study 1 (PURSUIT-Induction) was clinical response at Week 6. The major secondary endpoints were clinical remission, mucosal healing (improvement of endoscopic appearance of the mucosa), and the improvement in the IBDQ score, all at Week 6. The primary endpoint for UC Study 2 (PURSUIT-Maintenance) was maintenance of clinical response through Week 54. Selected major secondary endpoints included clinical remission at both Week 30 and Week 54 and mucosal healing at both Week 30 and Week 54.
In both studies, clinical response and clinical remission were defined based on the Mayo score, which consists of four subscores: stool frequency, rectal bleeding, findings of endoscopy, and physician's global assessment. Each subscore is rated on a scale from 0 to 3, indicating normal (0) to severe (3) activity. The Mayo score is the sum of the 4 subscores. Clinical response was defined as a decrease from Week 0 of induction in the Mayo score of ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1. Clinical remission was defined as a Mayo score ≤2 points, with no individual subscore >1. Improvement of endoscopic appearance of the mucosa (study endpoint, mucosal healing) was defined as a Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability).
In UC Study 2, patients were assessed for UC disease activity by partial Mayo score every 4 weeks (loss of response was confirmed by endoscopy). A patient who maintained response was in a state of continuous clinical response at each evaluation through Week 54. Similarly, a patient had to be in remission at both Weeks 30 and 54 (without demonstrating a loss of response at any time point through Week 54) to achieve durable remission.
Health-related quality of life was assessed using the IBDQ, SF-36 and the EQ-5D. The IBDQ is a questionnaire specifically designed for patients with inflammatory bowel disease. The SF-36 is a general health status questionnaire that has been widely used in various diseases and conditions to assess patients' physical and mental well being. The EQ-5D is a standardized non-disease specific instrument for describing and valuing health-related quality of life.
Approximately 63% (358/570) of patients, who were receiving SIMPONI at the beginning of the study extension (Week 56), remained on treatment through the end of the study (last SIMPONI administration at Week 212).
Study results: The results for clinical endpoints during induction treatment are based on patients randomized during the dose confirming part of UC Study 1 (PURSUIT-Induction, n=504). The results for clinical endpoints during maintenance treatment are based on patients from UC Study 2 (PURSUIT-Maintenance) who achieved clinical response with SIMPONI from previous induction with golimumab (n=456).
Clinical Response, Clinical Remission, and Improvement of Endoscopic Appearance of the Mucosa: In UC Study 1, a significantly greater percentage of patients in the SIMPONI group achieved clinical response, clinical remission and endoscopic improvement of the mucosa when compared to placebo at Week 6.
The data from UC Study 2 demonstrate that the proportion of patients who maintained clinical response through Week 54 was significantly greater in the SIMPONI 100 mg group compared with the placebo group. Additionally, the proportion of patients in clinical response who achieved clinical remission and improvement of endoscopic appearance of the mucosa at both Weeks 30 and 54 were significantly greater in the SIMPONI 100 mg group compared with the placebo group. (See Table 19.)
Click on icon to see table/diagram/imageMore SIMPONI-treated patients demonstrated sustained improvement of endoscopic appearance of the mucosa at both Week 30 and Week 54 in the 50 mg group (42%, nominal p<0.05) and 100 mg group (42%, p<0.005) compared with patients in the placebo group (27%).
Mayo Score: In UC Study 1 (PURSUIT-Induction), a greater reduction in the partial Mayo score was evident as early as Week 2 in the SIMPONI 200/100 mg group compared with the placebo group and this reduction was maintained through Week 6.
The reduced median partial Mayo score (at Week 0 of UC Study 2) was maintained in the SIMPONI 100 mg group through Week 52 and in the SIMPONI 50 mg group through Week 48; the median partial Mayo score in the placebo group increased after Week 8 and continued to increase over time to a value at Week 54 approaching the value prior to golimumab induction.
The proportion of subjects in UC Study 2 that maintained improvement in each Mayo subscore from Week 0 through Week 54 in UC Study 2 was greater in 100 mg group compared to the placebo group.
Among patients who entered the study extension, the proportion of subjects with inactive or mild disease activity as assessed by the Physician's global assessment subscore of the Mayo score was generally sustained through Week 216.
Health-related Quality of Life: In UC Study 1 (PURSUIT-Induction), the mean improvement from baseline in IBDQ score at Week 6 was significantly greater in the SIMPONI 200/100 mg group, 27.0 ± 33.72, compared with the placebo group, 14.8 ± 31.25; p<0.0001.
Pharmacokinetics: Following SC administration of SIMPONI to healthy subjects or patients with RA, the median time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. The systemic clearance of SIMPONI was estimated to be 6.9 ± 2.0 mL/day/kg, and mean volume of distribution 115 ± 19 mL/kg in healthy subjects; in patients with RA, the systemic clearance of SIMPONI was estimated to be 7.6 ± 2.0 mL/day/kg, and mean volume of distribution 151.1 ± 61 mL/kg. The volume of distribution for SIMPONI indicates that SIMPONI 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 RA, PsA, AS, or UC. Following SC administration of SIMPONI in healthy subjects, the following PK parameters were obtained as shown in Table 20. (See Table 20.)
Click on icon to see table/diagram/imageFollowing a single SC dose in healthy subjects, dose-proportional pharmacokinetics were observed over a dose range of 50 mg to 400 mg with both Cmax and area under the concentration-time curve (AUC) increased proportionally.
Following a single SC injection of 100 mg, the absorption of SIMPONI was similar in the upper arm, abdomen, and thigh, with a mean absolute bioavailability of 51%. Since SIMPONI exhibited approximately dose proportional PK following SC administration, the absolute bioavailability of the SIMPONI 50 mg or 200 mg dose is expected to be similar to the 100 mg dose.
When 50 mg SIMPONI was administered SC to patients with RA, PsA or AS every 4 weeks, serum concentrations reached steady-state by Week 12. With concomitant use of methotrexate, treatment with 50 mg SIMPONI every 4 weeks resulted in a median steady-state trough serum concentration of approximately 0.6 μg/mL in patients with active RA despite methotrexate therapy, and approximately 0.5 μg/mL in patients with active PsA and approximately 0.6 μg/mL in patients with AS. Patients with RA, PsA or AS who did not receive concomitant use of methotrexate had approximately 30% lower steady-state trough concentrations of SIMPONI than those who received SIMPONI with methotrexate. Concomitant use of methotrexate reduced the apparent clearance of SIMPONI by 36% after 6-month treatment with SIMPONI in patients with RA. However, population PK analysis indicated that concomitant use of nonsteroidal anti-inflammatory drugs, oral corticosteroids or sulfasalazine was not found to influence the apparent clearance of SIMPONI.
Steady-state mean trough serum golimumab concentrations in patients with nr-Ax SpA were comparable to those observed in patients with AS following subcutaneous administration of 50 mg golimumab every 4 week.
Following induction doses of 200 mg and 100 mg SIMPONI at Week 0 and 2 respectively, and maintenance doses of 100 mg SIMPONI every 4 weeks thereafter in patients with UC, serum golimumab concentrations reached steady-state approximately 14 weeks after the start of therapy. Treatment with 100 mg SIMPONI every 4 weeks during maintenance resulted in a mean steady-state trough serum concentration of approximately 1.8 ± 1.1 μg/mL.
Population pharmacokinetic analyses showed there was a trend toward higher apparent clearance of SIMPONI with increasing weight. As a result, patients with heavier weight tend to have lower steady-state trough concentrations of SIMPONI. However, across the RA, PsA, and AS populations, a treatment benefit from golimumab 50 mg was observed for all subgroups by weight quartiles with no meaningful differences in clinical efficacy among these subgroups. Treatment with the recommended dose regimens of SIMPONI in UC patients did not result in meaningful differences in clinical efficacy among the different weight subgroups, particularly among patients receiving the 100 mg maintenance dose. Therefore, there is no need to adjust the dosage of SIMPONI based on a patient's weight.
No gender-related pharmacokinetic differences were observed with SIMPONI after correction for patients' body weights. Pharmacokinetic parameters of SIMPONI were not influenced by age in adult patients. Patients with age ≥65 years had apparent clearance of SIMPONI similar to patients with age <65 years. No ethnicity-related pharmacokinetic differences were observed between Caucasians and Asians.
Patients who developed anti-SIMPONI antibodies generally had low trough steady-state serum concentrations of SIMPONI.
Special Populations and Conditions: Pediatrics: The safety and efficacy of SIMPONI have not been established in pediatric patients aged 17 years and younger.
Geriatrics: Pharmacokinetic parameters of SIMPONI were not influenced by age in adult patients. Patients with age ≥65 years had apparent clearance of SIMPONI similar to patients with age <65 years.
Gender: No gender-related pharmacokinetic differences were observed with SIMPONI after correction for patients' body weights.
Race: No ethnicity-related pharmacokinetic differences were observed between Caucasians and Asians.
Hepatic insufficiency: SIMPONI has not been studied in this patient population. No dose recommendation can be made.
Renal insufficiency: SIMPONI has not been studied in this patient population. No dose recommendation can be made.
Absorption: Following a single SC administration of SIMPONI to healthy subjects or patients with RA, the time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. A SC injection of 50 mg SIMPONI to healthy subjects produced a mean ± standard deviation maximum serum concentration (Cmax) of 3.2 ± 1.4 μg/mL. Both Cmax and area under the concentration-time curve (AUC) increased proportionally with doses over the range of 50 to 400 mg following a single SC administration.
Following a single SC injection of 100 mg in healthy subjects, the absorption of SIMPONI was similar in the upper arm, abdomen, and thigh, with a mean absolute bioavailability of 51%. Since SIMPONI exhibited approximately dose proportional PK following SC administration, the absolute bioavailability of a SIMPONI 50 mg or 200 mg dose is expected to be similar to the 100 mg dose.
Following a single IV administration of 2 mg/kg SIMPONI I.V., a mean Cmax of 44.4 ± 11.3 μg/mL was observed in patients with RA.
Distribution: Following a single IV administration, 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 for SIMPONI indicates that SIMPONI is distributed primarily in the circulatory system with limited extravascular distribution.
Metabolism: The exact metabolic pathway of SIMPONI is unknown.
Elimination: Following a single IV administration, the systemic clearance of SIMPONI 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.
Terminal half-life was consistent between IV and SC administration of SIMPONI. The terminal half-life was estimated to be 12 ± 3 days in healthy subjects and similar half-life was observed in patients with RA, PsA, AS, or UC.
After a 6-month treatment with SIMPONI by subcutaneous administration in patients with RA, concomitant use of methotrexate reduced the apparent clearance of SIMPONI by 36%; however, following IV administration, no appreciable effect of methotrexate on the clearance of SIMPONI was observed. Population PK analysis indicated that concomitant use of NSAIDs, oral corticosteroids or sulfasalazine did not influence the apparent clearance of SIMPONI following SC administration.
Population PK analyses showed that, following SC administration of SIMPONI, patients with higher C-reactive protein levels tended to have higher apparent clearance of SIMPONI. Patients with higher C-reactive protein levels were more likely to have lower trough serum concentrations of SIMPONI following SC administration of SIMPONI. In contrast, C-reactive protein level showed no effect on the clearance of SIMPONI following IV administrations of 2 mg/kg SIMPONI at Weeks 0, 4, and every 8 weeks thereafter.
Patients who developed anti-SIMPONI antibodies following SC or IV administration generally had low trough steady-state serum concentrations of SIMPONI.
Toxicology: Nonclinical toxicology studies include multiple-dose IV studies and single-dose and multiple-dose SC studies of up to 6 months duration, an embryo-fetal development study evaluating the maternal and fetal effects of golimumab treatment during pregnancy, and a prenatal and postnatal development study evaluating the maternal and neonatal effects of golimumab treatment during pregnancy and lactation. The developmental and reproductive toxicity of an analogous anti-mouse TNFα monoclonal antibody (mAb), cV1q, was also assessed and are included as additional supportive data for the development of golimumab. An in vitro human tissue cross-reactivity study was also conducted.
Results from nonclinical toxicology studies are summarized in Table 21. (See Table 21.)
Repeated Dose Toxicology Studies: Three repeated dose toxicity studies were conducted to support golimumab administration in patients. In the 6-month IV study, no abnormal findings considered golimumab-related were revealed at necropsy, except for a disseminated histoplasmosis infection found in one animal in the 25 mg/kg recovery group. This finding is not unexpected, as opportunistic infections are known risks of anti-TNF inhibitors and have been observed in human subjects treated with anti-TNF agents. In both the 6-month IV study and the 6-month SC study, there was a slight increase in the number of circulating lymphocytes. In the 6-month IV study there was a slight decrease in the humoral immune response to KLH. This reduction was not observed in the 6-month SC study where a different immunization protocol was used. The lymphocyte changes and slight reduction in immune response to KLH immunization are considered to be biological responses to TNFα inhibition and are not considered to be of toxicological significance.
Developmental and Reproductive Toxicity Studies: Golimumab administration to cynomolgus monkeys during pregnancy and lactation produced no adverse developmental effects, including no effects on the developing immune system. Fetuses were exposed to golimumab during gestation. In fetuses, golimumab acquired during gestation persisted in the infant serum for at least 6 months after birth. Golimumab was detected in the breast milk at concentrations that were approximately 350-fold lower than in the maternal serum concentrations.
In the mouse studies using cV1q, no toxicologically significant effects of anti-TNFα mAb treatment were detected on fertility, embryo-fetal, pre- and post-natal development and developmental immunotoxicity.
Genotoxicity: Genotoxicity studies have not been conducted with golimumab. Because of their large molecular size, mAbs are not expected to pass through the cellular and nuclear membranes and are not expected to gain access to or to interact with DNA or other chromosomal material.
Carcinogenicity: No carcinogenicity studies have been performed with golimumab.
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