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Simponi (Golimumab) - Description and Clinical Pharmacology

 
 



DESCRIPTION

SIMPONI (golimumab) is a human IgG1қ monoclonal antibody specific for human tumor necrosis factor alpha (TNFalpha) that exhibits multiple glycoforms with molecular masses of approximately 150 to 151 kilodaltons. SIMPONI was created using genetically engineered mice immunized with human TNF, resulting in an antibody with human-derived antibody variable and constant regions. SIMPONI is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses.

The SIMPONI drug product is a sterile solution of the golimumab antibody supplied as either a single dose prefilled syringe (with a passive needle safety guard) or a single dose prefilled autoinjector. The Type 1 glass syringe has a coated stopper. The fixed stainless steel needle (5 bevel, 27G, half-inch) is covered with a needle shield to prevent leakage of the solution through the needle and to protect the needle during handling prior to administration. The needle shield is made of a dry natural rubber containing latex.

SIMPONI does not contain preservatives. The solution is clear to slightly opalescent, colorless to light yellow with a pH of approximately 5.5. SIMPONI is provided in one strength: 50 mg of the golimumab antibody in 0.5 mL of solution. Each 0.5 mL of SIMPONI contains 50 mg of the golimumab antibody, 0.44 mg of L-histidine and L-histidine monohydrochloride monohydrate, 20.5 mg of sorbitol, 0.08 mg of polysorbate 80, and Water for Injection.

CLINICAL PHARMACOLOGY

Mechanism of Action

Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFalpha. This interaction prevents the binding of TNFalpha to its receptors, thereby inhibiting the biological activity of TNFalpha (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 TNFalpha 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. TNFalpha 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 administration in patients with RA, PsA, and AS.

Pharmacokinetics

Following subcutaneous (SC) administration of SIMPONI 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 to healthy subjects produced a mean maximum serum concentration (Cmax) of approximately 2.5 g/mL. SIMPONI 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 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 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 active RA, PsA or AS. By cross-study comparisons of mean AUCinf values following an IV or SC administration of SIMPONI, the absolute bioavailability of SC SIMPONI was estimated to be approximately 53%.

When 50 mg SIMPONI 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 SC every 4 weeks resulted in a mean steady-state trough serum concentration of approximately 0.4—0.6 g/mL in patients with active RA, approximately 0.5 g/mL in patients with active PsA, and approximately 0.8 g/mL in patients with active AS. Patients with RA, PsA and AS treated with SIMPONI 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 50 mg without MTX. The presence of MTX also decreased anti-golimumab antibody incidence from 7% to 2% [ see Adverse Reactions ]. For RA, SIMPONI 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.

Population PK analyses showed there was a trend toward higher apparent clearance of SIMPONI 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 MTX-experienced and TNF-blocker-naive patients (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 (50 mg and 100 mg). Therefore, there is no need to adjust the dosage of SIMPONI 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 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 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 antibodies generally had lower steady-state serum trough concentrations of SIMPONI.

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

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies of golimumab have not been conducted to evaluate its carcinogenic potential. Mutagenicity studies have not been conducted with golimumab. A fertility study conducted in mice using an analogous anti-mouse TNFalpha antibody showed no impairment of fertility.

CLINICAL STUDIES

Rheumatoid Arthritis

The efficacy and safety of SIMPONI 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 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 50 mg (n = 153), or SIMPONI 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 50 mg + background MTX (n = 89), SIMPONI 100 mg + background MTX (n = 89), or SIMPONI 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-naive and had not previously been treated with a biologic TNF-blocker. Patients were randomized to receive MTX (n = 160), SIMPONI 50 mg + MTX (n = 159), SIMPONI 100 mg + MTX (n = 159), or SIMPONI 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 and MTX achieved ACR responses at Week 14 (Studies RA-1 and RA-2) and Week 24 (Studies RA-1, 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 dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). In Studies RA-2 and RA-3, the SIMPONI 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 50 mg and control groups in Studies RA-1, RA-2, and RA-3. In the subset of patients who received SIMPONI 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 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 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 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.

Table 2. Studies RA-1, RA-2, and RA-3 Proportion of Patients with an ACR ResponseApproximately 78% and 58% of the patients received concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and NSAIDs, respectively, during the 3 pooled RA trials.
Study RA-1
Active RA previously treated with one or more doses of TNF-blockers
Study RA-2
Active RA, despite MTX
Study RA-3
Active RA, MTX Nave
Placebo

DMARDs 1
SIMPONI
50 mg

DMARDs
Background MTX SIMPONI 50 mg + Background MTX MTX SIMPONI
50 mg
+
MTX
NA Not applicable, as data was not collected at Week 14 in Study RA-3.
NN reflects randomized patients. 155 153 133 89 160 159
ACR 20
Week 14 18% 35% 33% 55% NA NA
Week 24 17% 34% 28% 60% 49% 62%
ACR 50
Week 14 6% 16% 10% 35% NA NA
Week 24 5% 18% 14% 37% 29% 40%
ACR 70
Week 14 2% 10% 4% 13% NA NA
Week 24 3% 12% 5% 20% 16% 24%Not significantly different from MTX monotherapy.

1 DMARDs in Study RA-1 included MTX, HCQ, and/or SSZ (about 68%, 8%, and 5% of patients received MTX, HCQ,and SSZ, respectively).

Table 3. Study RA-2 — Median Percent Improvement from Baseline in the Individual ACR Components at Weeks 14In Study RA-2, about 70% and 85% of patients received concomitant low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day) and/or NSAIDs during the trials, respectively.
Background MTX SIMPONI 50 mg +
Background MTX
Note: Baseline values are medians.
NN reflects randomized patients; actual number of patients evaluable for each endpoint may vary. 133 89
Number of swollen joints (0—66)
Baseline 12 13
Week 14 38% 62%
Number of tender joints (0—68)
Baseline 21 26
Week 14 30% 60%
Patient's assessment of pain (0—10)
Baseline 5.7 6.1
Week 14 18% 55%
Patient's global assessment of disease activity (0—10)
Baseline 5.3 6.0
Week 14 15% 45%
Physician's global assessment of disease activity (0—10)
Baseline 5.7 6.1
Week 14 35% 55%
HAQ score (0—3)
Baseline 1.25 1.38
Week 14 10% 29%
CRP (mg/dl)
Baseline 0.8 1.0
Week 14 2% 44%
Figure 1. Study RA - 2 — Percent of Patients Achieving ACR 20 Response by Visit: Randomized PatientsThe same patients may not have responded at each timepoint.

Physical Function Response in Patients with RA

In Studies RA-1 and RA-2, the SIMPONI 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 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 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 50 mg (n = 146), or SIMPONI 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 MTX, compared with placebo MTX, resulted in significant improvement in signs 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 dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). ACR responses observed in the SIMPONI-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 50 mg treatment also resulted in significantly greater improvement compared with placebo for each ACR component in Study PsA (Table 5). Treatment with SIMPONI resulted in improvement in enthesitis and skin manifestations in patients with PsA. However, the safety and efficacy of SIMPONI 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 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.

Table 4. Study PsA - Proportion of Patients with ACR Responses
Placebo MTX 1 SIMPONI
50 mg MTX
Bold text indicates primary endpoint
NN reflects randomized patients. 113 146
ACR 20
Week 14 9 % 51 %
Week 24 12 % 52 %
ACR 50
Week 14 2 % 30 %
Week 24 4 % 32 %
ACR 70
Week 14 1 % 12 %
Week 24 1 % 19 %

1 In Study PsA, about 48%, 16%, and 72% of the patients received stable doses of MTX (≤ 25 mg/day), low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and NSAIDs, respectively.

Table 5. Study PsA - Percent Improvement in ACR Components at Week 14
Placebo MTX 1 SIMPONI 50 mg MTX
Note: Baseline are median values
N N reflects randomized patients; actual number of patients evaluable for each endpoint may vary by timepoint 113 146
Number of swollen joints (0—66)
Baseline 10.0 11.0
Week 14 8 % 60 %
Number of tender joints (0—68)
Baseline 18.0 19.0
Week 14 0 % 54 %
Patient's assessment of pain (0—10)
Baseline 5.4 5.8
Week 14 -1 % 48 %
Patient's global assessment
of disease activity (0—10)
Baseline 5.2 5.2
Week 14 2 % 49 %
Physician's global assessment
of disease activity (0—10)
Baseline 5.2 5.4
Week 14 7 % 59 %
HAQ score (0—10)
Baseline 1.0 1.0
Week 14 0 % 28 %
CRP (mg/dL) (0—10)
Baseline 0.6 0.6
Week 14 0 % 40 %
1 In Study PsA, about 48%, 16%, and 78% of the patients received stable doses of MTX (≤ 25 mg/day), low dose corticosteroids (equivalent to ≤ 10 mg of prednisone a day), and NSAIDs, respectively.

Figure 2. Study PsA — Percent of ACR 20 PsA Responders by Visit: Randomized PatientsThe same patients may not have responded at each timepoint.

Physical Function Response in Patients with PsA

In Study PsA, SIMPONI 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 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 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 50 mg (n = 138), or SIMPONI 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 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 dose group (100 mg) compared to the lower SIMPONI dose group (50 mg). Table 7 shows the percent improvement in the components of the ASAS response criteria for the SIMPONI 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 50 mg + MTX group at the first assessment (Week 4) after the initial SIMPONI administration.

Table 6. Study AS — Proportion of ASAS Responders at Weeks 14 and 24
Placebo DMARDs 1 SIMPONI
50 mg DMARDs
Bold text indicates primary endpoint
NN reflects randomized patients. 78 138
Responders, % of patients
ASAS 20
Week 14 22% 59%
Week 24 23% 56%
ASAS 40
Week 14 15% 45%
Week 24 15% 44%

1 During the trial, the concomitant use of stable doses of DMARDS was as follows: MTX (21%), SSZ (25%), and HCQ (1%). About 16% and 89% of patients received stable doses of low dose oral steroids and NSAIDs during the trial, respectively.

Table 7. Study AS — Median Percent Improvement in ASAS Components at Week 14
Placebo DMARDs 1 SIMPONI 50 mg DMARDs
N N reflects randomized patients 78 138
ASAS components
Patient global assessment (0—10)
Baseline 7.2 7.0
Week 14 13% 47%
Total back pain (0—10)
Baseline 7.6 7.5
Week 14 9% 50%
BASFI (0—10)BASFI is Bath Ankylosing Spondylitis Functional Index
Baseline 4.9 5.0
Week 14 -3% 37%
Inflammation (0—10)Inflammation is the mean of two patient-reported stiffness self-assessments in the Bath AS Disease Activity Index (BASDAI)
Baseline 7.1 7.1
Week 14 6% 59%
1 During the trial, the concomitant use of stable doses of DMARDS was as follows: MTX (21%), SSZ (25%), and HCQ (1%). About 16% and 89% of patients received stable doses of low dose oral steroids and NSAIDs during the trial, respectively.

Figure 3. Study AS — Percent of AS Patients Achieving ASAS 20 Response by Visit: Randomized PatientsThe same patients may not have responded at each timepoint.

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