A Human Monoclonal Antibody Against Tumor Necrosis Factor-α

. 2009 Nov;34(11 Section 2):2–30.

A Human Monoclonal Antibody Against Tumor Necrosis Factor-α

PMCID: PMC2810175 PMID: 20140139

INTRODUCTION

The human immune system relies on a complex system of defense mechanisms to protect the body from infection.¹ This system consists of such cells as macrophages, dendritic cells, and natural killer (NK) lymphocytes to identify pathogens.¹

Under optimal circumstances, recognition of virulent pathogens prompts destruction of the pathogens by macrophages or NK cells or activation of a series of events to slow progression of infection. In addition, the adaptive immune system is activated.¹ Adaptive immunity is based on the generation of antigen receptors on T-and B-lymphocytes.¹ These lymphocytes express unique antigen receptors and have the ability to specifically identify diverse foreign antigens produced by the wide variety of pathogens. In addition, T-and B-lymphocytes have mechanisms to ensure nonreactivity to self antigens, and they contribute both specificity and immune memory to defend against pathogens.¹ Though their exact cause is unknown, a number of diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA), are thought to occur when the immune system attacks normal, healthy tissues in the body, causing inflammation and, over time, damage.¹

This Product Profiler reviews the evidence-based literature supporting the U.S. Food and Drug Administration-approved indications of SIMPONI^TM (golimumab) for the treatment of moderately to severely active RA, active AS, and active PsA.

DISEASE BACKGROUND

Rheumatoid Arthritis

RA is a chronic, multisystem disease characterized by persistent inflammatory synovitis that usually affects peripheral joints in symmetric distribution.¹ Synovial inflammation damages cartilage and causes bone erosion, which can result in diminished joint integrity. RA is estimated to affect approximately 1.3 million adults in the United States.² The prevalence of RA is approximately 2–3 times higher in women and increases with age,¹^–² with 80% of all patients developing RA between the ages of 35 and 50.¹

The etiology of RA is not clearly understood, although current research suggests that it may be a response to an infectious agent in a genetically susceptible host.¹ Micro vascular injury and increased production of synovial lining cells are thought to be the earliest clinical changes that affect the rheumatoid synovitis, followed by perivascular infiltration of mononuclear cells, which are predominantly myeloid cells before the onset of clinical symptoms. Symptoms are accompanied by the presence of T cells, and the synovium swells and protrudes into the joint space as the disease progresses¹ (Figure 1).

**Hand Affected by Rheumatoid Arthritis**

Copyright © Bart's Medical Library/Phototake Plus

Clinical manifestations of articular disease include pain in affected joints that may be greatest after periods of inactivity.¹ Extra-articular manifestations, including rheumatoid nodules, eye disease, and cardiopulmonary disease may occur. Although RA is a chronic condition, some affected individuals may experience fluctuations in disease activity, including intervals of remission.¹

RA is a cause of functional disability.³^,⁴ A 12-year, longitudinal study of 1,274 patients with RA revealed significant declines in functional ability. Fifty percent of patients with RA had functional disability scores indicative of moderate, severe, and very severe loss of functional abilities in 2, 6, and 10 years, respectively.³

This disease also imposes a significant economic burden relative to other chronic conditions, such as osteoarthritis (OA) and hypertension (HTN). A cost-of-illness study estimated annual direct medical costs in 2000 at $9,300 for RA, compared with $5,700 for OA and $3,900 for HTN.⁵ In this study, indirect costs associated with RA increased 5-fold relative to costs incurred by patients with OA, HTN, or both conditions.⁵

Drug therapy options. The use of biologic diseasemodifying antirheumatic drugs (DMARDs) has become more frequent in the treatment for RA, either as singleagent therapy or in combination with nonbiologic DMARDs.⁶ Multiple randomized, controlled trials have demonstrated that biologic tumor necrosis factor-alpha (TNF-α) inhibitors are effective in patients with RA when used alone,⁷^–⁹^,¹⁹^,³⁷ in combination with methotrexate,¹⁰^–¹⁷^,³¹^,³³^,³⁷^–³⁹ or in combination with other DMARDs.¹⁸^,³² The primary endpoint of interest in the majority of these trials has been a 20% improvement according to the American College of Rheumatology criteria (ACR20).⁸^,¹¹^–¹³^,¹⁷

Clinical challenges related to rheumatologic disease management persist, however. Because the clinical presentation can vary, treatment must be tailored to the individual, taking into account such factors as the severity of arthritis and individual lifestyles.²⁰ Moreover, current anti-TNF-α therapies differ in their affinity, stability, terminal half-life characteristics, route of administration, and frequency of dosing.²¹^–²⁴^,³⁰

Ankylosing Spondylitis

AS is an inflammatory disease with typical diagnosis occurring between ages 15 and 35.²⁵ Current estimates suggest that 350,000 to 1 million Americans are affected by AS.²⁵^,²⁶ The male-to-female prevalence is estimated to be up to 3 to 1.¹ Current evidence suggests that genetic factors are the primary cause of susceptibility to AS.¹ The pathogenesis of AS is not yet well understood, but it is considered to be an immune-mediated disease with a key role played by TNF-α.²⁵

AS most frequently affects the axial skeleton, and initial symptoms include dull, insidious pain affecting the lower lumbar or gluteal areas as well as early morning stiffness in the lower back that can persist for several hours.¹ AS also affects peripheral joints and extra-articular structures, with 25% to 35% of patients experiencing arthritis in the hips and shoulders and up to 30% affected by arthritis in other joints.¹ Other symptoms include neck pain and stiffness.¹

The clinical course of AS is variable with patients experiencing exacerbations of symptoms followed by periods of remission.¹ Disease progression is characterized by formation of syndesmophytes; postural changes, including lumbar or thoracic curvature; buttock atrophy; a forward stoop of the neck; or flexion contractures at the hips.¹

Psoriatic Arthritis

PsA is a chronic inflammatory arthritis that commonly affects individuals with plaque psoriasis, with prevalence estimated at about 11 percent in people with active psoriasis.¹^,²⁷ PsA also is considered to be an immune-mediated inflammatory disease characterized by penetration of the PsA synovium with T cells, B cells, macrophages, and upregulation of leukocyte homing receptors.¹ Some 60% to 70% of cases of PsA are preceded by development of psoriasis, with the onset of symptoms most frequently observed in individuals in their 30s and 40s.¹ Patients report pain, stiffness, and swelling in and around the joints.²⁸

PATHOPHYSIOLOGY

RA is an inflammatory condition that involves infiltration of the synovium primarily by CD4+ T cells, monocytes, and macrophages to produce multiple cytokines, including IL-1, IL-6, and TNF-α.²⁹ These are considered to be key cytokines that provoke the inflammatory responses observed in patients with RA.²⁹ CD4+ T cells also prompt the production of B cells that are responsible for the production of immunoglobulins, including rheumatoid factor.²⁹ TNF-α and IL-1 are stimulators of mesenchymal cells, which include synovial fibroblasts, osteoclasts, and chondrocytes. All of these contribute to the release of matrix metalloproteinases, which destroy tissue. IL-1 and TNF-α also inhibit the production of tissue inhibitors of metalloproteinases by synovial fibroblasts.²⁹ It has been suggested that the combined effects of these processes cause joint damage over time. TNF-α also is known to provoke development of osteoclasts, which are destructive to bone.²⁹

TNF-α is produced by the combined efforts of immune cells, including monocytes, macrophages, and T cells. TNF-α is a leading contributor to inflammatory reactions because of its effects as an autocrine stimulator and paracrine inducer of other inflammatory cytokines, including IL-1, IL-6, IL-8, and granulocyte-monocyte colony-stimulating factor. TNF-α also provokes inflammatory reactions through promotion of fibroblasts that express adhesion molecules, which interact with ligands on the surface of leukocytes. These interactions increase the transport of leukocytes to sites of inflammation, such as joints in patients with RA.²⁹

This description of the inflammatory process identifies key factors that contribute to the pathophysiology and progression of RA. In particular, TNF-α has been identified as an important target for pharmacologic therapy for RA.

References

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P T. 2009 Oct;34(11):4–5.

Description and Clinical Pharmacology

DESCRIPTION³⁰

SIMPONI^TM (golimumab) is a human IgG1κ monoclonal antibody specific for human tumor necrosis factor alpha (TNFα) that exhibits multiple glycoforms with molecular masses of approximately 150 to 151 kilodaltons. SIMPONI^TM was created using genetically engineered mice immunized with human TNF, resulting in an antibody with human-derived antibody variable and constant regions. SIMPONI^TM 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^TM 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 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^TM does not contain preservatives. The solution is clear to slightly opalescent, colorless to light yellow with a pH of approximately 5.5. SIMPONI^TM is provided in one strength: 50 mg of the golimumab antibody in 0.5 mL of solution. Each 0.5 mL of SIMPONI^TM 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 Action³⁰

Golimumab is a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNF-α. This interaction prevents the binding of TNF-α to its receptors, thereby inhibiting the biological activity of TNF-α (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. mumab did not lyse human monocytes expressing transmembrane TNF in the presence of complement or effector cells.

Elevated TNF-α levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases, such as RA, PsA, and AS. TNF-α 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 bio assays, including the expression of adhesion proteins responsible for leukocyte infiltration (E-selectin, inter cellular adhesion molecule [ICAM]-1 and vascular cell adhesion molecule-1) and the secretion of proinflammatory cytokines (interleukin [IL]-6, IL-8, G-CSF and GM-CSF).

Pharmacodynamics³⁰

In clinical studies, decreases in C-reactive protein (CRP), IL-6, matrix metalloproteinase 3, ICAM-1, and vascular endothelial growth factor were observed following SIMPONI^TM administration in patients with RA, AS, and PsA.

Pharmacokinetics³⁰

Following subcutaneous (SC) administration of SIMPONI^TM 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^TM to healthy subjects produced a mean maximum serum concentration (Cmax) of approximately 2.5 μg/mL. SIMPONI^TM 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^TM was estimated at 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^TM indicates that SIMPONI^TM 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 AUC_inf values following IV or SC administration of SIMPONI^TM, absolute bioavailability of SC SIMPONI^TM was estimated to be approximately 53%.

When 50 mg SIMPONI^TM 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 methotrexate (MTX), treatment with 50 mg SIMPONI^TM SC every 4 weeks resulted in a mean steady-state trough serum concentration of approximately 0.4–0.6 μg/mL in patients with active RA, approximately 0.5 μg/mL in patients with active PsA, and approximately 0.8 μg/mL in patients with active AS. Patients with RA, PsA and AS treated with SIMPONI^TM 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^TM 50 mg without MTX. The presence of MTX decreased anti-golimumab antibody incidence from 7% to 2%. For RA, SIMPONI^TM 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.

Population PK analyses indicated that concomitant use of NSAIDs, oral corticosteroids, or sulfasalazine did not influence the apparent clearance of SIMPONI^TM.

Population PK analyses showed a trend toward higher apparent clearance of SIMPONI^TM with increasing weight. However, across 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-naïve patients did show evidence of a reduction in clinical efficacy with increasing body weight, but this effect was observed for both tested doses of SIMPONI^TM (50 mg and 100 mg). Therefore, there is no need to adjust the dosage of SIMPONI^TM 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^TM were not influenced by age in adult patients. Patients age ≥65 years had apparent clearance of SIMPONI^TM similar to patients 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^TM antibodies generally had lower steady-state serum trough concentrations of SIMPONI^TM.

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

P T. 2009 Oct;34(11):6–19.

Summary of Key Published Clinical Trials

RHEUMATOID ARTHRITIS

Golimumab, a Human Antibody to TNF-α Given by Monthly Subcutaneous Injections, in Active Rheumatoid Arthritis Despite Methotrexate Therapy: The GO-FORWARD Study

GO-FORWARD, a phase 3 multicenter, randomized, double-blind, placebo-controlled trial included a controlled phase through Week 52 that is being followed by an open-label extension up to 5 years.³¹ Patients were enrolled at 60 investigational centers in 12 countries.³¹

Four hundred forty-four patients with moderately to severely active RA, age 18 and older, met the eligibility criteria and were randomly assigned to receive study treatment. Patients were eligible to participate if they had:

A diagnosis of RA according to the revised 1987 criteria of the American College of Rheumatology (ACR) for at least 3 months prior to screening for participation
Been on a stable dose of MTX ≥15 mg/week but ≤ 25 mg/week during the 4 weeks prior to screening for participation
Active RA, defined as ≥4 swollen joints out of a total of 66 and ≥4 tender joints out of a total of 68
And at least two of the following:
- ○ CRP ≥1.5 mg/dL or erythrocyte sedimentation rate (ESR) ≥28 mm/hour
- ○ Morning stiffness that persisted for at least 30 minutes
- ○ Bone erosion confirmed by radiographs or magnetic resonance imaging
- ○ Anti-cyclic citrullinated peptide (anti-CCP) antibody-positive or rheumatoid-factor (RF) positive

Patients were excluded from the study if they had:

Known hypersensitivity to human immunoglobulin proteins or other components of golimumab
Previously been treated with any anti-TNF-α agent, rituximab, natalizumab, or cytotoxic agent
Been treated with anakinra, DMARDs other than MTX, or IV, intramuscular, or intra-articular corti-costeroids in the 4 weeks preceding the first dose of study medication, or alefacept or efalizumab in the preceding 3 months.

Methods and Trial Endpoints

Figure 2 illustrates the trial design profile, including patient randomization and completion rates for study endpoints by treatment arm. Patients completed a 4-week run-in period between screening for study eligibility and randomization. During this time, all patients were supplied over-encapsulated MTX capsules at their prestudy stable dose. At the conclusion of the run-in phase, patients’ eligibility for study participation was reassessed, and those who still met the requisite criteria were randomly assigned in a 3:3:2:2 ratio to 1 of 4 groups, as described in Table 1. Because the approved dose regimen for SIMPONI^TM is 50 mg adminstered monthly, the results from this treatment cohort are presented in comparison to placebo. All patients continued their prestudy stable dose of MTX except those in Group 2, who were switched to sham MTX at randomization with no washout period prior to treatment initiation.³¹

**GO-FORWARD Patient Disposition Through Week 24**

Source: Keystone 2009.³¹ Reproduced with permission from BMJ Publishing Group Ltd.

TABLE 1.

GO-FORWARD Treatment Cohorts

Cohort	(n)	Description
Group 1	133	SC placebo injection+MTX
Group 2	133	Golimumab 100 mg SC injection + placebo capsules
Group 3	89	Golimumab 50 mg SC injection+MTX
Group 4	89	Golimumab 100 mg SC injection+MTX

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MTX=methotrexate; SC=subcutaneous.

Source: Keystone 2009³¹

Multiple endpoints assessed patient response to treatment, including the ACR response criteria (ACR20/50/70). Physical function was evaluated with the Health-Assessment Questionnaire Disability Index (HAQ-DI). A minimally clinically important change was defined as a reduction from baseline HAQ-DI ≥0.25.³¹

A primary study endpoint included the proportion of patients who achieved an ACR20 response at Week 14. ACR20 data were analyzed with a 2-sided chi-square test using P=0.05 to determine significance.³¹ Additionally, improvement in HAQ-DI scores were evaluated from baseline to Week 24.³¹

Results

Selected baseline clinical and demographic characteristics of the patients are summarized in Table 2. The majority of patients had been treated with corticosteroids and/or DMARDs other than MTX prior to enrollment in this study.³¹ The median MTX dose was 15 mg/week at baseline.

TABLE 2.

Selected Baseline Demographic and Clinical Characteristics of GO-FORWARD Patients

			Golimumab+MTX

Characteristic	Group 1 (n=133)	Group 2 (n=133)	Group 3 (n=89)	Group 4 (n=89)	Groups 3 and 4 combined (n=178)

Female, n (%)	109 (82)	105 (78.9)	72 (80.9)	72 (80.9)	144 (80.9)

Age in years, median (range)	52 (42–58)	51 (42–59)	52 (43–57)	50 (45–56)	51 (44–57)

Duration of RA in years, median (range)	6.5 (3.1–11.9)	5.9 (2.4–12.2)	4.5 (2.1–9.7)	6.7 (2.4–14.3)	5.3 (2.1–12.3)

Swollen joints, n, median (range)^a	12 (8–19)	11 (8–17)	13 (8–22)	12 (8–18)	12.5 (8–18)

Tender joints, n, median (range)^b	21 (14–34)	22 (14–32)	26 (16–39)	23 (15–33)	24.5 (15–37)

Anti-CCP antibodies, n (%)	107 (80.5)	106 (79.7)	72 (80.9)	68 (76.4)	140 (78.7)

Rheumatoid factor, n (%)	108 (81.2)	111 (83.5)	77 (86.5)	75 (84.3)	152 (85.4)

CRP, mg/dL, median (range)	0.8 (0.3–2.0)	0.9 (0.4–2.5)	1.0 (0.4–2.8)	0.9 (0.4–2.4)	0.95 (0.4–2.4)

HAQ-DI, median (range)^c	1.25 (.75, 1.75)	1.38 (.88, 1.88)	1.38 (1.00, 1.88)	1.38 (.88, 1.88)	1.38 (.88, 1.88)

MTX dose, mg/week, median (range)	15.0 (15, 20)	15.0 (15, 20)	15.0 (15, 20)	15.0 (15, 20)	15.0 (15, 20)

Duration prior MTX use, n (%)
• <1 year	33 (24.8)	30 (22.6)	20 (22.5)	17 (19.1)	37 (20.8)
• ≥ 1 to <3 years	30 (22.6)	41 (30.8)	32 (36.0)	31 (34.8)	63 (35.4)
• ≥ 3 years	68 (51.1)	62 (46.6)	37 (41.6)	40 (44.9)	77 (43.3)

Patients taking corticosteroids, n (%)	87 (65.4)	90 (67.7)	67 (75.3)	62 (69.7)	129 (72.5)
• Prednisone or equivalent dose, median (range), mg/day	7.3 (5, 10)	7.5 (5, 10)	7.5 (5, 10)	7.5 (5, 10)	7.5 (5, 10)

Prior DMARD use other than MTX, n (%)	94 (70.7)	101 (75.9)	70 (78.7)	67 (75.3)	137 (77.0%)

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^a

Possible range 0–66.

^b

Possible range 0–68.

^c

Possible range 0–3.

Anti-CCP=anti-cyclic citrullinated peptide; CRP=C-reactive protein; DMARD=disease-modifying antirheumatic drug; HAQ-DI=Health Assessment Questionnaire-Disability Index; MTX=methotrexate; RA=rheumatoid arthritis.

Source: Keystone 2009³¹

The primary endpoint of an ACR20 response was obtained by 33.1% of patients in Group 1 at Week 14 compared with 55.1% of those in Group 3 (P<0.001). The ACR20 response rates by treatment group are presented in Figure 3.³¹

There also were significantly greater improvements from baseline in median HAQ-DI scores at Week 24 between treatment groups, with an improvement of −0.13 for Group 1 compared with −0.38 in Group 3 (P<0.001). Among the patients in Group 1, 38.6% achieved a reduction in their baseline HAQ-DI score ≥0.25 at Week 24, and 68.2% of patients in Group 3 (P<0.001) achieved this endpoint (P<0.001).³¹

Secondary endpoints included achieved ACR20 responses at Week 24, and ACR50 and ACR70 responses at Weeks 14 and 24. At Week 24, 59.6% of golimumab 50 mg-treated patients had maintained ACR20, compared to 27.8% of placebo subjects (P<0.001). ACR50 and ACR70 responses were 37.1% and 20.2% among golimumab 50 mg-treated patients, compared to 13.5% and 5.3% of placebo subjects, respectively (P<0.001 for both comparisons).³¹

Safety Considerations

Rates of adverse events (AEs) and serious AEs (SAEs) by treatment group are summarized in Table 3. Golimumab was generally well tolerated.³¹ Infections were observed in 27.3% of golimumab-treated patients (123/450) vs. 27.6% of those who received MTX only (37/134). Injection-site reactions were observed in 4.4% of golimumab-treated patients (20/450) vs. 3.0% (4/134) of those who received MTX only.³¹ One person in the golimumab 100 mg group died from a serious infection.³¹ Injection-site reactions were generally mild or moderate, and none led to discontinuation of the study drug.³¹ One patient in the placebo group and three in the treatment groups had malignancies.³¹ No cases of active tuberculosis (TB) or opportunistic infections were observed.³¹ Antibody formation was too in frequent to evaluate effect on clinical efficacy and safety.³¹

TABLE 3.

Summary of Select Adverse Events Through Week 24 by GO-FORWARD Treatment Group

Assessment	Group 1 (n=134)	Group 2 (n=133)	Group 3 (n=212)	Group 4 (n=105)
Any adverse event, n (%)	89 (66.4)	98 (73.7)	87 (41.0)	78 (74.3)
Events per patient year (95% CI)	4.72 (4.16–5.33)	2.74 (2.45–3.05)	1.75 (1.53–1.99)	2.82 (2.48–3.19)
Serious adverse events, n (%)	5 (3.7)	8 (6.0)	9 (4.2)	13 (12.4)
Events per patient year (95% CI)	0.09 (0.03–0.21)	0.11 (0.06–0.19)	0.08 (0.04–0.14)	0.18 (0.10–0.30)
Any infection, n (%)	37 (27.6)	50 (37.6)	34 (16.0)	39 (37.1)
Serious infection, n (%)	1 (0.7)	4 (3.0)	2 (0.9)	5 (4.8)
Injection-site reactions, n (%)	4 (3.0)	10 (7.5)	5 (2.4)	5 (4.8)

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CI=confidence interval, MTX=methotrexate.

Source: Keystone 2009³¹

Golimumab in Patients With Active Rheumatoid Arthritis After Treatment With Tumor Necrosis Factor α Inhibitors (GO-AFTER Study): A Multi-centre, Randomised, Double-blind, Placebo-controlled, Phase III Trial

GO-AFTER evaluated the efficacy and safety of golimumab for the treatment of active RA among patients who previously had been treated with one or more TNF inhibitors.³² This phase 3, multicenter, randomized, double-blind, placebo-controlled trial enrolled 461 patients from 82 sites in 10 countries.

Patients were 18 years or older with a diagnosis of active RA according to ACR criteria with active RA characterized by at least four swollen and four tender joints. In addition, all patients had been treated with at least one dose of a TNF-inhibitor including etanercept, adalimumab, or infliximab, with the last dose administered at least 8 weeks (etanercept and adalimumab) or 12 weeks (infliximab) before the first dose of golimumab. Concomitant treatment with a DMARD (MTX, sulfasalazine, or hydroxychloroquine, alone or in combination) was permitted but patients were required to have tolerated this therapy for at least 12 weeks and maintained a stable dose of the medication for 4 or more weeks prior to study initiation. In addition, patients treated with a DMARD were required to maintain their pretrial stable dose for the duration of the study.³² Patients were allowed to take oral corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) if patients’ doses had been stable for at least 2 weeks before the first dose of the study drug.

Patients were ineligible if they had:³²

Inflammatory diseases other than RA
A serious adverse reaction to a previous TNF-α agent
Previous treatment with natalizumab or rituximab
Received previous treatment with anakinra less than 4 weeks or alefacept or efalizumab less than 3 months before receiving the first dose of study drug
A history of latent or active granulomatous infection (not including latent TB) that had been prophylactically treated in the past 3 years
A BCG vaccination less than 12 months, an opportunistic infection less than 6 months, or a serious infection less than 2 months before screening for study enrollment
A history of certain health conditions, including congestive heart failure; severe, progressive, uncontrolled, renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, psychiatric, or cerebral disease; a history of chronic infections; demyelinating disease; or an organ transplantation or malignancy in the 5 years prior to study enrollment.

Methods and Trial Endpoints

Patients meeting study eligibility criteria were randomly assigned in a 1:1:1 ratio to subcutaneous injections of placebo, golimumab 50 mg, or golimumab 100 mg once every 4 weeks.³² Because the approved dose regimen for SIMPONI^TM is 50 mg administered monthly, the results from this treatment cohort are presented in comparison to placebo. An overview of the patient disposition is presented in Figure 4 (page 9).

**GO-AFTER Patient Disposition Through Week 24**

*Patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy.

Source: Smolen 2009.³² Reproduced with permission.

The primary study endpoint was achievement of a 20% or greater improvement in ACR criteria for RA (ACR20) at Week 14.³² Secondary endpoints included ACR20 at Week 24, ACR50 and ACR70 at Weeks 14 and 24, and HAQ-DI scores at Weeks 14 and 24.

Results

Clinical and demographic characteristics of patients who met study eligibility criteria and were randomized to 1 of the 3 treatment groups are presented in Table 4. The median number of swollen and tender joints was 14 and 26, respectively, for all enrolled patients at baseline. More than 95% of the patients had been treated for at least 4 weeks with at least one TNF inhibitor. Twenty-five percent had been treated with two agents in this class, and 9% of patients had received three TNF inhibitors prior to study enrollment.³² Approximately two thirds of all patients had been treated with MTX.³²

TABLE 4.

Selected Baseline Demographic and Clinical Characteristics of GO-AFTER Patients

		Golimumab
Characteristic	Placebo (n=155)	50 mg (n=153)	100 mg (n=153)
Female, n (%)	132 (85)	113 (74)	122 (80)
Age in years, median (range)	54 (46–64)	55 (46–63)	55 (47–61)
Duration of RA in years, median (range)	9.8 (4.9–17.6)	9.6 (5.6–17.2)	8.7 (5.3–13.2)
Swollen joints, n, median (range)^a	14 (9–23)	14 (9–25)	13 (9–19)
Tender joints, n, median (range)^b	26 (15–43)	27 (16–42)	26 (15–38)
Anti-CCP antibodies, n (%)	112 (72)	107 (72)	107 (73)
Rheumatoid factor, n (%)^c	110 (73)	108 (72)	105 (72)
CRP concentration, mg/L median (range)	10 (3–21)	8 (3–27)	8 (3–23)
HAQ-DI assessment of physical function, median (range)^d	1.8 (1.3–2.1)	1.6 (1.1–2.0)	1.5 (1.0–2.0)
MTX treatment, number (%)^e	102 (66)	103 (67)	100 (66)
Hydroxychloroquine treatment, number (%)^f	12 (8)	13 (9)	10 (7)
Sulfasalazine treatment, number (%)	6 (4)	4 (3)	12 (8)
No MTX, hydroxychloroquine, sulfasalazine treatment, number (%)	48 (31)	44 (29)	45 (29)

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^a

Possible range 0–66.

^b

Possible range 0–68.

^c

Data supplied for 151, 149, and 146 patients on placebo, 50 mg golimumab, and 100 mg golimumab, respectively.

^d

Possible range 0–3.

^e

Data provided for 152 patients on 100 mg golimumab; 12, 5, and 4 patients on placebo, 50 mg golimumab, and 100 mg golimumab, respectively, discontinued methotrexate before beginning the study.

^f

Data provided for 152 patients on 50 mg golimumab.

CCP=cyclic citrullinated peptide, CRP=C-reactive protein; HAQ-DI=Health Assessment Questionnaire-Disability Index; MTX=methotrexate; VAS=visual analog scale.

Source: Smolen 2009³²

Patients in the golimumab 50 mg group were more likely to achieve significant ACR20 improvement at week 14 compared with patients in the placebo group. Specifically, 35% of patients administered golimumab 50 mg achieved the ACR20 endpoint, compared with 18% of those in the placebo arm (P=0.0006).³² The proportion of patients achieving ACR20 in the combined golimumab group was higher for those treated with concomitant DMARDs than those not administered DMARDs.³² Significantly higher proportions of patients administered golimumab 50 mg achieved ACR20 by week 4 compared with patients in the placebo group (Figure 5).³²

**GO-AFTER: ACR20 Responders by Treatment Group**

Error bars=standard error. Dashed line indicates primary endpoint of ACR20 assessment at Week 14.

Source: Smolen 2009.³² Reproduced with permission.

Patients in the golimumab 50 mg cohort also experienced a median 13.3% improvement in physical function, as assessed by HAQ-DI, compared with 0% in the placebo group at Week 24 (P=0.0003).

Safety Considerations

Rates of adverse events and serious adverse events are detailed in Table 5. Overall occurrence of any AE was observed in 78%, 72%, and 66% of patients in the golimumab 100 mg, placebo, and golimumab 50 mg groups, respectively (Table 5). AEs affecting more than 5% of patients in the combined golimumab dose groups included upper respiratory tract infections, nasopharyngitis, cough, rheumatoid arthritis, and diarrhea.³² The highest rate of infections was evident for patients treated with golimumab 100 mg (36%), compared with 35% of those in the golimumab 50 mg group and 33% of patients administered placebo. The highest rate of injection-site reactions (11%) was evident for the golimumab 100 mg group, with rates of 6% and 4% for the golimumab 50 mg and placebo arms, respectively. None of the injection-site reactions were considered severe and none prompted any patients to discontinue study participation.³² No patients in the study developed active TB or opportunistic infection. One death occurred during the study, and three patients (one each in the placebo, golimumab 50 mg, and golimumab 100 mg groups) developed malignancies.³² Among study participants in whom antibody formation could be assessed, increased antibodies to golimumab occurred in 3% of patients (8/264).³²

TABLE 5.

Summary of Select Adverse Events Through Week 24 by GO-AFTER Treatment Group

			Golimumab
Adverse Event (AE)	Placebo (n=155)	Placebo to golimumab 50 mg (n=72)^a	50 mg (n=152)^b	50 mg to 100mg (n=41)^a	100 mg (n=152)^b	Combined (n=304)
Any AE, n (%)	112 (72)	30 (42)	101 (66)	15 (37)	119 (78)	226 (74)
Serious AEs, n (%)	15 (10)	3 (4)	11 (7)	1 (2)	7 (5)	19 (6)
Any infection, n (%)	51 (33)	11 (15)	53 (35)	3 (7)	55 (36)	111 (37)
Any serious infections	5 (3)	1 (1)	5 (3)	0 (0)	1 (1)	6 (2)
Injection-site reactions	6 (4)	3 (4)	9 (6)	2 (5)	16 (11)	27 (9)

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^a

Changes in dosing at Week 16 due to early escape provisions in trial design.

^b

One patient who never received treatment was excluded.

Source: Smolen 200932

Golimumab, a Human Anti-Tumor Necrosis Factor α Monoclonal Antibody, Injected Subcutaneously Every Four Weeks in Methotrexate-Naïve Patients With Active Rheumatoid Arthritis [GO-BEFORE]

GO-BEFORE evaluated the efficacy and safety of golimumab in adult patients with active RA who were methotrexate-naïve and had not been previously treated with a biologic TNF-blocker.³³ This phase 3, multicenter, randomized, double-blind, placebo-controlled trial enrolled 637 patients at 90 investigational sites. It included a 52-week controlled phase that is being followed by a 5-year open-label extension.³³

Patients were eligible to participate if they had:

A diagnosis of RA according to the ACR criteria for at least 3 months before administration of the study agent
Not received more than three weekly doses of oral MTX as treatment of RA
Active RA, defined as at least four swollen joints and at least four tender joints at screening and baseline
And met at least two of the following criteria at screening or baseline or both:
- ○ CRP level ≥1.5 mg/dL or erythrocyte sedimentation rate (ESR) ≥28 mm/hour
- ○ Morning stiffness lasting at least 30 minutes
- ○ Bone erosion confirmed by radiographs and/or MRI
- ○ Anti-CCP antibody-positive or RF-positive

Patients were excluded from GO-BEFORE if they had:

Previously received TNF blockers, rituximab, natalizumab, or cytotoxic agents
Been treated with anakinra in the 4 weeks preceding the first dose of study medication, or alefacept or efalizumab in the preceding 3 months

Methods and Trial Endpoints

Patients were randomly assigned to 1 of 4 treatment groups, as depicted in Figure 6 with their disposition through Week 24. Golimumab or matching placebo was administered subcutaneously at Week 0 and every 4 weeks thereafter. Active MTX or placebo MTX was provided in identical opaque capsules. For patients receiving MTX, MTX dosage began at 10 mg/week at Week 0 and increased by 2.5 mg every 2 weeks to 20 mg/week at Week 8.

**GO-BEFORE Patient Disposition Through Week 24**

Source: Emery 2009.³³ Reproduced with permission from the American College of Rheumatology

The primary endpoint in GO-BEFORE was the percentage of patients achieving an ACR50 response at Week 24. ACR20 and ACR70 responses also were evaluated.

Results

Selected baseline clinical and demographic characteristics of the patients are shown in Table 6. At baseline, the median duration of RA ranged from 1.0 to 1.8 years across the four treatment groups.

TABLE 6.

Selected Baseline Demographic and Clinical Characteristics of GO-BEFORE Patients

Characteristic	Group 1 (n=160)	Group 2 (n=159)	Group 3 (n=159)	Group 4 (n=159)

Female, n (%)	134 (84)	134 (84)	135 (85)	125 (79)

Age in years, mean (median)	49 (50)	48 (49)	51 (51)	50 (50)

Duration of RA in years, mean (median)	2.9 (1.2)	4.1 (1.8)	3.5 (1.0)	3.6 (1.3)

Swollen joints, mean (median)^a	15 (11)	15 (12)	16 (13)	16 (14)

Tender joints, mean (median)^b	27 (26)	27 (25)	29 (26)	27 (26)

C-reactive protein, mg/dL, mean (median)	2.6 (1.4)	2.6 (1.3)	2.4 (1.3)	2.4 (1.3)

HAQ-DI, mean (median)^c	1.5 (1.5)	1.6 (1.7)	1.5 (1.5)	1.5 (1.6)

MTX dosage, mean mg/week (median)
Week 0	10 (10)	0 (0)	10 (10)	10 (10)
Week 23	19 (20)	0 (0)	19 (20)	19 (20)

Previous systemic corticosteroids, n (%)	109 (68)	101 (64)	111 (70)	104 (65)

Prior DMARD use (other than MTX), n (%)	83 (52)	93 (59)	80 (50)	91 (57)

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^a

Possible range 0–66

^b

Possible range 0–68

^c

Possible range 0–3

Anti-CCP=anti-cyclic citrullinated peptide; DMARD=disease-modifying antirheumatic drug; HAQ-DI=Health Assessment Questionnaire-Disability Index; MTX=methotrexate; RA=rheumatoid arthritis.

Source: Emery 2009³³

The primary endpoint, ACR50 response at Week 24 (Figure 7), was met by 40.3% of the group receiving golimumab 50 mg plus MTX versus 29.4% of the group receiving placebo plus MTX (P=.042).³³ In addition, an ACR20 response at Week 24 was achieved by 61.6% and 49.4% of the golimumab 50 mg/MTX and the placebo/MTX groups, respectively (P=.028).³³ An ACR70 response at Week 24 was achieved by 23.9% and 15.6% of the golimumab 50 mg/MTX and the placebo/MTX groups, respectively, but the difference was not statistically significant (P=.064).³³

**Percentage of Patients Achieving ACR50 Response**

Safety Considerations

AEs through Week 24 are summarized in Table 7. The most commonly reported AEs in the groups receiving MTX plus golimumab 50 mg or 100 mg were nausea, upper respiratory tract infection, increased aspartate aminotransferase level, increased alanine aminotransferase level, dyspepsia, and headache.³³

TABLE 7.

Summary of Adverse Events Through Week 24 by GO-BEFORE Treatment Group

Assessment	Group 1 (n=160)	Group 2 (n=157)	Group 3 (n=158)	Group 4 (n=159)

Any adverse event, n (%)	116 (73)	107 (68)	129 (82)	121 (76)
Serious adverse events, n (%)	11 (7)	5 (3)	10 (6)	10 (6)

Any infection, n (%)	52 (33)	55 (35)	54 (34)	50 (31)

Serious infections, n (%)	3 (2)	2 (1)	2 (1)	7 (4)

Injection-site reactions, n (%)	3 (2)	17 (11)	7 (4)	14 (9)

Discontinuation of study agent due to adverse event, n (%)	2 (1)	1 (1)	6 (4)	7 (4)
Subcutaneous study agent	3 (2)	1 (1)	6 (4)	9 (6)
Oral study agent

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Source: Emery 2009³³

There were four malignancies in this study, including two cases of breast cancer (groups 1 and 3), one case of Hodgkin’s lymphoma (group 4), and one case of lip squamous cell carcinoma (group 1).³³

One woman in the group receiving golimumab 50 mg plus MTX was diagnosed with TB of the spine 33 days after the Week 8 administration of golimumab. She discontinued the study agent, received TB treatment, and underwent spinal surgery. Prior to study entry she had back pain and radiographic evidence of spinal involvement.³³

Two patients died during the study period: one in group 3 who committed suicide on Day 113 (29 days after the last golimumab dose) and one in group 4 who experienced cardiorespiratory arrest after surgery on Day 34 (33 days after the last golimumab dose).³³

None of the injection-site reactions were considered severe or serious or resulted in discontinuation of the study agent.³³

Golimumab, a New Human Tumor Necrosis Factor–α Antibody, Administered Every Four Weeks as a Subcutaneous Injection in Psoriatic Arthritis. Twenty-four-week efficacy and safety results of a randomized, placebo-controlled study [GO-REVEAL]

A phase 3, multicenter, randomized, double-blind, placebo-controlled trial provided an evaluation of the efficacy and safety of 24 weeks of treatment with golimumab for PsA.³⁴ The GO-REVEAL trial randomized 405 patients with active PsA from 58 sites located in the United States, Canada, and Europe. Active PsA was defined by the presence of three or more swollen joints and three or more tender joints, negative rheumatoid factor, at least one subtype of PsA, and the presence of plaque psoriasis with a lesion ≥2 cm in diameter. Patients were excluded from the study if they had previously been treated with TNF inhibitors, rituximab, natalizumab, or cytotoxic agents. Patients currently receiving stable doses of MTX, NSAIDs, and corticosteroids (prednisone ≤10 mg/day) were eligible for study participation.³⁴

Methods and Endpoints

Patients were randomized in a 1:1.3:1.3 ratio by a centralized interactive voice response system to receive subcutaneous injections of placebo, golimumab 50 mg, or golimumab 100 mg at weeks 0, 4, 8, 12, 16, and 20. Because the approved dose regimen for SIMPONI^TM is 50 mg administered monthly, the results from this treatment cohort are presented in comparison to placebo. Patient disposition through Week 24 is shown in Figure 8. Randomization was stratified by the use of MTX at study enrollment.³⁴

**GO-REVEAL Patient Disposition Through Week 24**

Source: Emery 2009.³³ Reproduced with permission.

The primary study endpoint, reported herein, was the proportion of patients who met the ACR 20% improvement criteria (ACR20) at Week 14. Investigators also assessed secondary endpoints, including ACR50 and ACR70 responses, the extent and severity of psoriatic skin involvement using the Psoriasis Area and Severity Index (PASI), and physical function response according to HAQ.³⁴

Analysis of the primary endpoint included all patients randomized to treatment, and differences in treatment response were evaluated with the Cochran-Mantel-Haenszel test for categorical variables and analysis of variance on van der Waerden normal scores for continuous variables. All statistical tests were two-sided and tested at a 0.05 level of significance. Stratification variables included treatment group and use of MTX at baseline. Statistically significant differences between the combined golimumab dose and placebo groups were required before comparisons between golimumab 50 mg and placebo were calculated. Safety analyses included all patients who received at least one dose of study drug.³⁴

Results

Patients were randomized to the 3 treatment groups with baseline clinical and demographic characteristics presented in Table 8 (page 15). Study discontinuation rates were 11% for the placebo group and 4% of patients randomized to either golimumab group.³⁴

TABLE 8.

GO-REVEAL Selected Baseline Demographic and Clinical Characteristics by Treatment Group

Characteristic	Placebo (n=113)	Golimumab 50 mg (n=146)	Golimumab 100 mg (n=146)

Male, number (%)	69 (61)	89 (61)	86 (59)

Caucasian, number (%)	110 (97)	141 (97)	142 (97)

Age in years, mean (SD)	47.0 (10.6)	45.7 (10.7)	48.2 (10.9)

PsA duration in years, mean (SD)	7.6 (7.9)	7.2 (6.8)	7.7 (7.8)

Swollen joints, mean (SD)	13.4 (9.8)	14.1 (11.4)	12.0 (8.4)

Tender joints, mean (SD)	21.9 (14.7)	24.0 (17.1)	22.5 (15.7)

CRP, mg/dL, mean (SD)	1.3 (1.6)	1.3 (1.6)	1.4 (1.8)

PsA subtype, number (%)
• Distal interphalangeal joint arthritis	16 (14)	24 (16)	22 (15)
• Arthritis mutilans	0 (0)	2 (1)	1 (1)
• Asymmetric peripheral arthritis	27 (24)	44 (30)	49 (34)
• Polyarticular arthritis with no rheumatoid nodules	58 (51)	62 (43)	56 (38)
• Spondylitis with peripheral arthritis	12 (11)	14 (10)	18 (12)

PASI,^a mean (SD)	8.4 (7.4)	9.8 (8.6)	11.1 (9.5)

MTX treatment, number (%)	54 (48)	71 (49)	69 (47)

Oral corticosteroid treatment, number (%)	19 (17)	19 (13)	27 (18)

NSAID treatment, number (%)	88 (78)	110 (75)	110 (75)

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^a

Possible score 0–72.

MTX=methotrexate; NSAIDs=nonsteroidal anti-inflammatory drugs; PASI=Psoriasis Area and Severity Index.

Source: Kavanaugh 2009.³⁴

Among patients treated with golimumab 50 mg, 51% met the endpoint of ACR20 at Week 14 compared with 9% of those in the placebo group (P<0.001) (Figure 9). Treatment response was not significantly associated with MTX treatment (P=0.66).³⁴ Among secondary endpoints, 52% of patients administered golimumab 50 mg achieved ACR20 at Week 24 versus 12% in the placebo group (P<0.001), and 56% achieved PASI-75 at Week 24 vs. 1% in the placebo group (P<0.001).³⁴

Safety Considerations

Safety assessments through Week 24 showed that 65% of all patients treated with both doses of golimumab and 59% of those in the placebo group experienced at least one AE (Table 9); the most frequent AEs were upper respiratory infections, seen in 10% of the golimumab combined dose group and 6% of patients in the placebo group. Similar rates of nasopharyngitis were reported (10% and 4% of the combined golimumab and placebo groups, respectively.) Serious infections were more frequent in the placebo group (two cases of pneumonia, one case of cellulitis, and one case of urosepsis) while one serious infection (abscess) was reported in the golimumab 50 mg group. One serious infection (sepsis/cholecystitis) was reported in the golimumab 100 mg group. No cases of active TB were observed. Rates of injection site reactions were comparable among all treatment groups. None of the injection-site reactions were severe or serious, and most frequently presented as erythema. Three malignancies occurred, including 2 cases of basal cell carcinoma and 1 prostate cancer; all of these affected patients in the golimumab 100 mg group and reflected an incidence of 2.32 per 100 patient-years compared with an incidence of 0 per 100 patient-years in the placebo group. AEs resulted in study discontinuation for 3% of patients treated with either dose of golimumab and 4% of patients in the placebo arm by Week 24.³⁴

TABLE 9.

Summary of Select Adverse Events through Week 24 by GO-REVEAL Treatment Group

Event	Placebo (n=113)	Golimumab 50 mg (n=146)	Golimumab 100 mg (n=146)	Golimumab combined doses (n=292)
Total adverse events, number (%)	67 (59)	99 (68)	95 (65)	196 (67)
Serious adverse events, number (%)	7 (6)	3 (2)	4 (3)	7 (2)
Serious infections, number (%)	4 (4)	1 (<1)	1 (<1)	2 (<1)
Injection-site reactions, number (%)	3 (3)	4 (3)	6 (4)	10 (3)
Markedly abnormal ALT level, number (%)	4 (4)	3 (2)	0 (0)	3 (1)
Markedly abnormal AST level, number (%)	3 (3)	2 (1)	0 (0)	2 (<1)
Markedly abnormal total bilirubin level, number (%)	2 (2)	4 (3)	2 (1)	6 (2)

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ALT=alanine aminotransferase; AST=aspartate aminotransferase; URTI=upper respiratory tract infection.

Source: Kavanaugh 2009³⁴

Safety events reported after Week 24 (including an open-label extension after Week 52) were two deaths in the golimumab 50 mg cohort (one from small cell lung cancer and one as a result of a climbing accident). Malignancies reported during this phase included one case of colon cancer in a patient assigned to the 50 mg group through early escape, one case of small cell lung cancer in the 100 mg group, and two cases of basal cell carcinomas (one in the 50 mg group and one in a patient who crossed over from the 50 mg group to the 100 mg group). Additionally, one patient in the 100 mg group developed liver histoplasmosis.

ANKYLOSING SPONDYLITIS

Efficacy and Safety of Golimumab for Ankylosing Spondylitis: Results of a Randomized, Double-Blind, Placebo-Controlled, Phase III Trial [GO-RAISE]

GO-RAISE evaluated the safety and efficacy of golimumab for the treatment of 356 patients with active AS in a phase 3 randomized, double-blind, placebo-controlled multicenter study conducted at 57 investigational sites in the United States, Canada, Europe, and Asia.³⁵

Patients eligible for study enrollment included adults who had AS for 3 months or longer before study initiation, a Bath AS Disease Activity Index (BASDAI) score of 4 or greater, a spinal pain assessment score ≥4 on a 0–10 cm visual analog scale, and an inadequate response to current or prior treatment with NSAIDs or DMARDs. Patients currently receiving NSAIDs were required to have been on continuous therapy for three months at the highest recommended dose or unable to receive a full 3-month course of full-dose NSAID therapy due to intolerance, toxicities, or contraindications. Chest radiographs within 3 months preceding randomization and screening for latent TB were required for all study participants. Initiation of treatment for TB prior to or simultaneously with administration of the first dose of study drug was required for patients who had evidence of latent TB.³⁵

Concurrent treatment with MTX, sulfasalazine, hydroxychloroquine, corticosteroids, and NSAIDs at stable doses was permitted during the course of the study. Patients requiring treatment with the following agents were excluded: systemic immunosuppressive agents; DMARDs other than MTX, sulfasalazine, or hydroxychloroquine within 4 weeks of first study treatment; leflunomide within 4 weeks of first study treatment; alefacept or efalizumab within 3 months before first administration of study treatment; and any previous treatment with anti-TNF-α therapy, rituximab, natalizumab, or cytotoxic medications. Additional exclusion criteria included, but were not limited to, complete ankylosis of the spine, serious infection in the 2 months prior to study initiation, active or latent TB, opportunistic infection within 6 months of screening, a transplanted organ, and various comorbid health conditions including hepatitis, HIV, malignancy, congestive heart failure, and multiple sclerosis.³⁵

Methods and Trial Endpoints

Patients were randomly assigned in a 1:1.8:1.8 ratio to receive placebo, golimumab 50 mg, or golimumab 100 mg for 24 weeks (Figure 10). Because the approved dose regimen for SIMPONI^TM is 50 mg administered monthly, the results from this treatment cohort are presented in comparison to placebo. Both golimumab and placebo were administered as SC injections once every 4 weeks. The randomization was stratified by investigational site and CRP level (≤1.5 mg/dL or >1.5 mg/dL).³⁵

**GO-RAISE Patient Disposition Through Week 24**

Source: Inman 2008.³⁵ Reproduced with permission of John Wiley & Sons, Inc.

The primary study endpoint was the proportion of patients who achieved at least a 20% improvement in the ASssessment in Ankylosing Spondylitis (ASAS) International Working Group criteria (ASAS20) at Week 14, with secondary endpoints including achievement of a 40% in ASAS (ASAS40), among others.³⁵

The primary efficacy analysis was based on comparison between treatment groups with the Cochrane-Mantel-Haenszel test stratified by CRP level (≤1.5 mg/dL vs. >1.5 mg/dL). A logistic regression analysis was performed on the following factors as predictors of ASAS20 response at Week 14: placebo versus either dose of golimumab, screening CRP level (≤1.5 mg/dl or > 1.5 mg/dl), treatment with DMARDs (yes or no), body weight, and duration of AS.³⁵

Results

Patients’ clinical and demographic characteristics were well matched across treatment groups (Table 10).³⁵

TABLE 10.

Selected Baseline Characteristics by GO-RAISE Treatment Group

Characteristic Median (range), unless noted	Placebo (n=78)	Golimumab 50 mg (n=138)	Golimumab 100 mg (n=140)	Golimumab groups combined (n=278)

Male, n (%)	55 (70.5)	102 (73.9)	98 (70.0)	200 (71.9)

Age, years	41.0 (31–50)	38.0 (30–47)	38.0 (29–46)	38.0 (29–46)

Years since inflammatory back pain first occurred	16 (6–24)	11 (6–19)	11 (5.0–18.5)	11 (6–19)

Years since symptoms of spondyloarthritis first occurred^*	16 (5–25)	11 (6–18)	9.5 (4–18)	11 (5–18)

Years since diagnosis of AS	7.25 (2.8–18.6)	5.15 (1.6–11.6)	5.2 (1.50–13.25)	5.2 (1.5–12.3)

HLA-B27 positive, n (%)	66 (84.6)	112 (81.8)	118 (84.3)	230 (83.0)

CRP, mg/dL, median (interquartile range)	1.15 (0.30–2.40)	1.10 (0.50–2.50)	0.90 (0.40–2.50)	1.00 (0.40–2.50)
• ≤1.5 mg/dL, no (%)	46 (59.0)	79 (57.2)	81 (57.9)	160 (57.6)
• >1.5 mg/dL, no (%)	32 (41.0)	59 (42.8)	59 (42.1)	118 (42.4)

BASDAI (0–10 scale)	6.6 (5.7–7.7)	6.6 (5.6–7.6)	7 (6.0–7.9)	6.8 (5.7–7.7)

BASFI (0–10 scale)	4.9 (3.5–6.8)	5 (3.2–6.7)	5.4 (3.4–7.3)	5.2 (3.2–6.9)

BASMI (0–10 scale)	4 (2–5)	3 (2–4)	3 (2–5)	3 (2–5)

Patients taking MTX, n (%)	15 (19.2)	29 (21.0)	28 (20.0)	57 (20.5)
• MTX dosage, mg/week	15 (12.5–15)	12.5 (10–15)	12.5 (10–15)	12.5 (10–15)

Patients taking sulfasalazine, n (%)	24 (30.8)	33 (23.9)	37 (26.4)	70 (25.2)
• dosage, gm/day	2 (1.3–2)	2 (1–2)	2 (1–2)	2 (1–2)

Patients taking hydroxychloroquine, n (%)	2 (2.6)	2 (1.4)	1 (0.7)	3 (1.1)
• dosage, mg/day	250 (200–300)	300 (200–400)	400 (400–400)	400 (200–400)

Patients taking corticosteroids, n (%)	13 (16.7)	26 (18.8)	18 (12.9)	44 (15.8)
• Prednisone or equivalent dosage, mg/day	7.5 (5–10)	6.3 (5–7.5)	5.0 (2.5–7.5)	5.0 (5–7.5)

Patients taking NSAIDs, n (%)	72 (92.3)	124 (89.9)	123 (87.9)	247 (88.8)

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^*

Spondylarthritis symptoms include back pain, uveitis, dactylitis, enthesitis, peripheral arthritis, or inflammatory bowel disease.

BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASFI=Bath Ankylosing Spondylitis Functional Index; BASMI=Bath Ankylosing Spondylitis Metrology Index; CRP=C-reactive protein; MTX=methotrexate; NSAIDs=nonsteroidal inflammatory drugs.

Source: Inman 2008³⁵

Among patients treated with golimumab, 59.4% of those receiving the 50 mg dose demonstrated an ASAS20 response at Week 14, whereas only 21.8% of those in the placebo group achieved a similar response (P<0.001 for both comparisons) (Figure 11). The logistic regression revealed that treatment group (P<0.001), CRP level (P=0.0062), and body weight (P=0.0140) were significant predictors of ASAS20 responses and that treatment with DMARDs and duration of time elapsed since diagnosis of AS were not significantly associated with ASAS20 scores. Subgroup analyses revealed that the significant improvements obtained from golimumab were sustained for diverse gender, race, age, geographic, and body weight groups, with the exception of patients weighing more than 87 kg in the golimumab 50 mg group (in the latter group, the percentage of patients with an ASAS20 response was not statistically significant compared to placebo).³⁵ At Week 24, 55.8% of 50 mg golimumab-treated patients had achieved ASAS20 and 43.5% had achieved ASAS40, compared to 23.1% and 15.4% of placebo subjects, respectively (Figure 11).³⁵

**GO-RAISE Patients Achieving ASAS Responses at Weeks 14 and 24**

*Numbers in cohorts changed at Week 16 due to early escape provisions in trial design.

Source: Inman 2008.³⁵ Reproduced with permission of John Wiley & Sons, Inc.

Safety Considerations

At the Week 24 assessment, 85.6% of patients in the combined golimumab groups had at least one AE compared to 79.9% of patients in the all-golimumab group, which included patients treated with placebo who met the criteria for early escape. More frequent occurrences of nasopharyngitis, upper respiratory infections, fatigue, headache, diarrhea, injection-site erythema, and elevated liver enzymes were reported for patients in the combined golimumab group compared with those in the placebo arm. Rates of SAEs were comparable among the different treatment arms through Week 24, with such events reported for 3.6% of patients in the 50 mg group, 6.4% of those administered the 100 mg dose, 5.4% in the combined golimumab groups, and 6.5% for patients treated with placebo. Through Week 24, three patients had serious infections. In the placebo group, one patient had gastro intesinal inflammation, and in the 100 mg group, one patient had chronic otitis media and one had mononucleosis. Two patients, one in the placebo group and one in the 100 mg group, had basal cell carcinoma. No opportunistic infections, cases of TB, or deaths were observed.

Table 11 presents the type and rates of AE and SAE through Week 24.³⁵

TABLE 11.

Summary of Select Adverse Events Through Week 24 by GO-RAISE Treatment Group^a

			Golimumab
Assessment	Placebo (n=77)	Placebo to golimumab 50 mg^b (n=41)	50 mg (n=138)	50 mg to 100 mg^b (n=25)	100 mg (n=140)	Combined (n=278)	All golimumab (n=319)
Any adverse event, n (%)	59 (76.6)	17 (41.5)	117 (84.8)	14 (56.0)	120 (85.7)	238 (85.6)	255 (79.9)
Any serious adverse event, n (%)	5 (6.5)	0 (0)	5 (3.6)	1 (4.0)	9 (6.4)	15 (5.4)	15 (4.7)
Any infection, n (%)	28 (36.4)	9 (22)	64 (46.4)	5 (20)	68 (48.6)	135 (48.6)	144 (45.1)
Any serious infection, n (%)	1 (1.3)	0 (0)	0 (0)	0 (0)	2 (1.4)	2 (0.7)	2 (0.6)
Injection-site reaction, n (%)	2 (2.6)	0 (0)	12 (8.7)	3 (12)	9 (6.4)	23 (8.3)	23 (7.2)

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^a

Except where otherwise indicated, values are the number (%) of patients.

^b

Changes in dosing at Week 16 due to early escape provisions in trial design.

Source: Inman 2008³⁵

P T. 2009 Oct;34(11):20–28.

P&T Committee Considerations

P&T committees must consider a number of issues before making formulary decisions. Criteria may include efficacy, drug safety, the need for the agent, potential for inappropriate use, side effects, availability of alternative agents, and cost. This section evaluates P&T considerations that may apply to SIMPONI^TM (golimumab).

INDICATIONS AND USAGE³⁰

Rheumatoid Arthritis

SIMPONI^TM, in combination with methotrexate, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis.

Psoriatic Arthritis

SIMPONI^TM, alone or in combination with methotrexate, is indicated for the treatment of adult patients with active psoriatic arthritis.

Ankylosing Spondylitis

SIMPONI^TM is indicated for the treatment of adult patients with active ankylosing spondylitis.

EFFICACY

Clinical Studies

Rheumatoid Arthritis

The efficacy and safety of SIMPONI^TM were evaluated in three 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^TM 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.³⁰

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^TM 50 mg (n=153), or SIMPONI^TM 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.³⁰

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^TM 50 mg+background MTX (n=89), SIMPONI^TM 100 mg+background MTX (n=89), or SIMPONI^TM 100 mg monotherapy (n=133). The use of other DMARDs including SSZ, HCQ, cytotoxic agents, or other biologics was prohibited.³⁰

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^TM 50 mg+MTX (n=159), SIMPONI^TM 100 mg+MTX (n=159), or SIMPONI^TM 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.³⁰

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 24.³⁰

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 three pooled RA trials.³⁰

In the three RA trials, a greater percentage of patients treated with the combination of SIMPONI^TM 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^TM dose group (100 mg) compared to the lower SIMPONI^TM dose group (50 mg). In Studies RA-2 and RA-3, the SIMPONI^TM monotherapy groups were not statistically different from the MTX monotherapy groups in ACR responses. In the subset of patients who received SIMPONI^TM 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^TM 50 mg+MTX group (n=103) compared with 17%, 6%, and 2%, respectively, in the placebo+MTX group (n=107). ACR 20 responses were observed in 38% of patients in the SIMPONI^TM 50 mg+MTX group at the first assessment (Week 4) after the initial SIMPONI^TM administration.³⁰

In Studies RA-1 and RA-2, the SIMPONI^TM 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^TM 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.³⁰

Psoriatic Arthritis

The safety and efficacy of SIMPONI^TM were evaluated in a multicenter, 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. 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^TM 50 mg (n=146), or SIMPONI^TM 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 24.³⁰

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.³⁰

SIMPONI^TM±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. There was no clear evidence of improved ACR response with the higher SIMPONI^TM dose group (100 mg) compared to the lower SIMPONI^TM dose group (50 mg). ACR responses observed in the SIMPONI^TM -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^TM 50 mg treatment also resulted in significantly greater improvement compared with placebo for each ACR component. Treatment with SIMPONI^TM resulted in improvement in enthesitis and skin manifestations in patients with PsA. However, the safety and efficacy of SIMPONI^TM in the treatment of patients with plaque psoriasis has not been established.³⁰

ACR 20 responses were observed in 31% of patients in the SIMPONI^TM 50 mg+MTX group at the first assessment (Week 4) after the initial SIMPONI^TM administration.³⁰

SIMPONI^TM 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^TM 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.³⁰

Ankylosing Spondylitis

The safety and efficacy of SIMPONI^TM were evaluated in a multicenter, 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. 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 randomly assigned to placebo (n=78), SIMPONI^TM 50 mg (n=138), or SIMPONI^TM 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.³⁰

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 24.³⁰

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%).³⁰

SIMPONI^TM±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. There was no clear evidence of improved ASAS response with the higher SIMPONI^TM dose group (100 mg) compared to the lower SIMPONI^TM dose group (50 mg).³⁰

ASAS 20 responses were observed in 48% of patients in the SIMPONI^TM 50 mg group at the first assessment (Week 4) after the initial SIMPONI^TM administration.³⁰

SAFETY

P&T committee members should be aware of the following warnings, precautions, drug interactions, and other considerations associated with use of SIMPONI^TM.

Contraindications³⁰

None.

Boxed Warnings³⁰

Patients treated with SIMPONI^TM are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

SIMPONI^TM should be discontinued if a patient develops a serious infection. Reported infections include:

Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before SIMPONI^TM use and during therapy. Treatment for latent infection should be initiated prior to SIMPONI^TM use.
Invasive fungal infections, including histoplasmosis, coccidioidomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric antifungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
Bacterial, viral, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with SIMPONI^TM should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI^TM, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Warnings and Precautions³⁰

Serious Infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving TNF-blockers including SIMPONI^TM. Among opportunistic infections, tuberculosis, histoplasmosis, aspergillosis, candidiasis, coccidioidomycosis, listeriosis, and pneumocystosis were the most commonly reported with TNF-blockers. Patients have frequently presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of SIMPONI^TM and these biologic products is not recommended.

Treatment with SIMPONI^TM should not be initiated in patients with an active infection, including clinically important localized infections. The risks and benefits of treatment should be considered prior to initiating SIMPONI^TM in patients:

With chronic or recurrent infection;
Who have been exposed to tuberculosis;
With a history of an opportunistic infection;
Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or
With underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with SIMPONI^TM. SIMPONI^TM should be discontinued if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with SIMPONI^TM should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

In controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, serious infections were observed in 1.4% of SIMPONI^TM-treated patients and 1.3% of control-treated patients. In the controlled Phase 3 trials through Week 16 in patients with RA, PsA, and AS, the incidence of serious infections per 100 patient-years of follow-up was 5.4 (95% CI: 4.0, 7.2) for the SIMPONI^TM group and 5.3 (95% CI: 3.1, 8.7) for the placebo group. Serious infections observed in SIMPONI^TM-treated patients included sepsis, pneumonia, cellulitis, abscess, tuberculosis, invasive fungal infections, and hepatitis B infection.

Tuberculosis. Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating SIMPONI^TM and periodically during therapy.

Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating SIMPONI^TM, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).

Anti-tuberculosis therapy should also be considered prior to initiation of SIMPONI^TM in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Tuberculosis should be strongly considered in patients who develop a new infection during SIMPONI^TM treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis.

In the controlled and uncontrolled portions of the Phase 2 RA and Phase 3 RA, PsA, and AS trials, the incidence of active TB was 0.23 and 0 per 100 patient-years in 2,347 SIMPONI^TM-treated patients and 674 placebo-treated patients, respectively. Cases of TB included pulmonary and extra pulmonary TB. The overwhelming majority of the TB cases occurred in countries with a high incidence rate of TB.

Invasive Fungal Infections. For SIMPONI^TM-treated patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

Hepatitis B Virus Reactivation. The use of TNF-blockers including SIMPONI^TM has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.

Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including SIMPONI^TM, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. Patients who are carriers of HBV and require treatment with TNF-blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy.

In patients who develop HBV reactivation, TNF-blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely.

Malignancies

The risks and benefits of TNF-blocker treatment including SIMPONI^TM should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy.

In the controlled portions of clinical trials of TNF-blockers including SIMPONI^TM, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. During the controlled portions of the Phase 2 trials in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of lymphoma per 100 patient-years of follow-up was 0.21 (95% CI: 0.03, 0.77) in the combined SIMPONI^TM group compared with an incidence of 0 (95% CI: 0, 0.96) in the placebo group. In the controlled and uncontrolled portions of these clinical trials in 2,347 SIMPONI^TM-treated patients with a median follow-up of 1.4 years, the incidence of lymphoma was 3.8-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). Patients with RA and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy.

During the controlled portions of the Phase 2 trial in RA, and the Phase 3 trials in RA, PsA and AS, the incidence of malignancies other than lymphoma per 100 patient-years of follow-up was not elevated in the combined SIMPONI^TM group compared with the placebo group. In the controlled and uncontrolled portions of these trials, the incidence of malignancies, other than lymphoma, in SIMPONI^TM-treated patients was similar to that expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race).

In controlled trials of other TNF-blockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener’s granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory 1-year clinical trial evaluating the use of 50, 100 and 200 mg of SIMPONI^TM in 309 patients with severe persistent asthma, 6 patients developed malignancies other than NMSC in the SIMPONI^TM groups compared to none in the control group. Three of the 6 patients were in the 200 mg SIMPONI^TM group.

Congestive Heart Failure

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. SIMPONI^TM has not been studied in patients with a history of CHF and SIMPONI^TM should be used with caution in patients with CHF. If a decision is made to administer SIMPONI^TM to patients with CHF, these patients should be closely monitored during therapy, and SIMPONI^TM should be discontinued if new or worsening symptoms of CHF appear.

Demyelinating Disorders

Use of TNF-blockers has been associated with cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS). While no trials have been performed evaluating SIMPONI^TM in the treatment of patients with MS, another TNF-blocker was associated with increased disease activity in patients with MS. Therefore, prescribers should exercise caution in considering the use of TNF-blockers including SIMPONI^TM in patients with CNS demyelinating disorders including MS.

Use with Abatacept and Anakinra

In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including SIMPONI^TM and abatacept is not recommended.

Use with Anakinra

Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including SIMPONI^TM, is not recommended.

Hematologic Cytopenias

There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. Although, there were no cases of severe cytopenias seen in the SIMPONI^TM clinical trials, caution should be exercised when using TNF-blockers, including SIMPONI^TM, in patients who have significant cytopenias.

Vaccinations

Patients treated with SIMPONI^TM may receive vaccinations, except for live vaccines. No data are available on the response to live vaccination or the risk of infection, or transmission of infection after the administration of live vaccines to patients receiving SIMPONI^TM. In the Phase 3 PsA study, after pneumococcal vaccination, a similar proportion of SIMPONI^TM-treated and placebo-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. In both SIMPONI^TM-treated and placebo-treated patients, the proportions of patients with response to pneumococcal vaccine were lower among patients receiving MTX compared with patients not receiving MTX. The data suggest that SIMPONI^TM does not suppress the humoral immune response to the pneumococcal vaccine.

Adverse Reactions³⁰

Clinical Studies Experience

The safety data described below are based on 5 pooled, randomized, double-blind, controlled Phase 3 trials in patients with RA, PsA, and AS (Studies RA-1, RA-2, RA-3, PsA, and AS). These 5 trials included 639 control-treated patients and 1659 SIMPONI^TM-treated patients including 1089 with RA, 292 with PsA, and 278 with AS. The proportion of patients who discontinued treatment due to adverse reactions in the controlled Phase 3 trials through Week 16 in RA, PsA and AS was 2% for SIMPONI^TM-treated patients and 3% for placebo-treated patients. The most common adverse reactions leading to discontinuation of SIMPONI^TM in the controlled Phase 3 trials through Week 16 were sepsis (0.2%), alanine aminotransferase increased (0.2%), and aspartate aminotransferase increased (0.2%).

The most serious adverse reactions were:

Serious Infections (see Warnings and Precautions)
Malignancies (see Warnings and Precautions)
Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 RA, PsA and AS trials through Week 16, occurring in 7% and 6% of SIMPONI^TM-treated patients as compared with 6% and 5% of control-treated patients, respectively.

Infections. In controlled Phase 3 trials through Week 16 in RA, PsA, and AS, infections were observed in 28% of SIMPONI^TM-treated patients compared to 25% of control-treated patients.

Liver enzyme elevations. There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of SIMPONI^TM in patients with RA, PsA, and AS through Week 16, ALT elevations ≥5 × ULN occurred in 0.2% of control-treated patients and 0.7% of SIMPONI^TM treated patients and ALT elevations ≥3 × ULN occurred in 2% of control-treated patients and 2% of SIMPONI^TM-treated patients. Since many of the patients in the Phase 3 trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between golimumab and liver elevation is not clear.

Autoimmune Disorders and Autoantibodies. The use of TNF-blockers has been associated with the formation of autoantibodies and, rarely, with the development of a lupus-like syndrome. In the controlled Phase 3 trials in patients with RA, PsA, and AS through Week 14, there was no association of SIMPONI^TM treatment and the development of newly positive anti-dsDNA antibodies.

Injection Site Reactions. In controlled Phase 3 trials through Week 16 in RA, PsA and AS, 6% of SIMPONI^TM-treated patients had injection site reactions compared with 2% of control-treated patients. The majority of the injection site reactions were mild and the most frequent manifestation was injection site erythema. In controlled Phase 2 and 3 trials in RA, PsA, and AS, no patients treated with SIMPONI^TM developed anaphylactic reactions.

Psoriasis: New-onset and exacerbation. Cases of new onset psoriasis, including pustular psoriasis and palmo-plantar psoriasis, have been reported with the use of TNF-blockers, including SIMPONI^TM. Cases of exacerbation of pre-existing psoriasis have also been reported with the use of TNF-blockers. Many of these patients were taking concomitant immunosuppressants (e.g., MTX, corticosteroids). Some of these patients required hospitalization. Most patients had improvement of their psoriasis following discontinuation of their TNF-blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF-blocker. Discontinuation of SIMPONI^TM should be considered for severe cases and those that do not improve or that worsen despite topical treatments.

Immunogenicity. Antibodies to SIMPONI^TM were detected in 57 (4%) of SIMPONI^TM-treated patients across the Phase 3 RA, PsA and AS trials through Week 24. Similar rates were observed in each of the three indications. Patients who received SIMPONI^TM with concomitant MTX had a lower proportion of antibodies to SIMPONI^TM than patients who received SIMPONI^TM without MTX (approximately 2% versus 7%, respectively). Of the patients with a positive antibody response to SIMPONI^TM in the Phase 2 and 3 trials, most were determined to have neutralizing antibodies to golimumab as measured by a cell-based functional assay. The small number of patients positive for antibodies to SIMPONI^TM limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures.

The data above reflect the percentage of patients whose test results were considered positive for antibodies to SIMPONI^TM in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SIMPONI^TM with the incidence of antibodies to other products may be misleading.

The SIMPONI^TM full prescribing information lists all adverse reactions that occurred at a rate of 1% or higher.

Drug Interactions³⁰

Methotrexate

For the treatment of RA, SIMPONI^TM should be used with MTX. Since the presence or absence of concomitant MTX did not appear to influence the efficacy or safety of SIMPONI^TM in the treatment of PsA or AS, SIMPONI^TM can be used with or without MTX in the treatment of PsA and AS.

Biologic Products for RA, PsA, and AS

An increased risk of serious infections has been seen in clinical RA studies of other TNF-blockers used in combination with anakinra or abatacept, with no added benefit; therefore, use of SIMPONI^TM with abatacept or anakinra is not recommended. A higher rate of serious infections has also been observed in RA patients treated with rituximab who received subsequent treatment with a TNF-blocker. There is insufficient information to provide recommendations regarding the concomitant use of SIMPONI^TM and other biologic products approved to treat RA, PsA, or AS.

Live Vaccines

Live vaccines should not be given concurrently with SIMPONI^TM.

Cytochrome P450 Substrates

The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNF) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of SIMPONI^TM in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

Use in Specific Populations³⁰

Pregnancy

Pregnancy Category B – There are no adequate and well-controlled studies of SIMPONI^TM in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether SIMPONI^TM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SIMPONI^TM should be used during pregnancy only if clearly needed.

An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (360 times greater than the maximum recommended human dose-MHRD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus.

A pre-and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (860 times and 310 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates. Golimumab was present in the neonatal serum from the time of birth and for up to six months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants.

Nursing Mothers

It is unknown whether SIMPONI^TM is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from SIMPONI^TM, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

In the pre-and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400-fold lower than the maternal serum concentrations.

Pediatric Use

Safety and effectiveness of SIMPONI^TM in pediatric patients less than 18 years of age have not been established.

Geriatric Use

In the Phase 3 trials in RA, PsA, and AS, there were no overall differences in SAEs, serious infections, and AEs in SIMPONI^TM-treated patients ages 65 or older (N=155) compared with younger SIMPONI^TM-treated patients. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with SIMPONI^TM.

Overdosage³⁰

In a clinical study, five patients received protocol-directed single infusions of 10 mg/kg of intravenous SIMPONI^TM without serious adverse reactions or other significant reactions. The highest-weight patient was 100 kg, and therefore received a single intravenous infusion of 1,000 mg of SIMPONI^TM. There were no SIMPONI^TM overdoses in the clinical studies.

DOSAGE, ADMINSTRATION, FORMS, STRENGTH

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis³⁰

The SIMPONI^TM dose regimen is 50 mg administered by SC injection once a month.

For patients with RA, SIMPONI^TM should be given in combination with methotrexate, and for patients with PsA or AS, SIMPONI^TM may be given with or without methotrexate or other nonbiologic DMARDs. For patients with RA, PsA, or AS, corticosteroids, nonbiologic DMARDs, and/or NSAIDs may be continued during treatment with SIMPONI^TM.

Monitoring to Assess Safety³⁰

Prior to initiating SIMPONI^TM and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection.

General Considerations for Administration³⁰

SIMPONI^TM is intended for use under the guidance and supervision of a physician. After proper training in SC injection technique, a patient may self-inject with SIMPONI^TM if a physician determines that it is appropriate. Patients should be instructed to follow the directions provided in the Medication Guide of the Full Prescribing Information. To ensure proper use, allow the prefilled syringe or autoinjector to sit at room temperature outside the carton for 30 minutes prior to SC injection. Do not warm SIMPONI^TM in any other way.

Prior to administration, visually inspect the solution for particles and discoloration through the viewing window. SIMPONI^TM should be clear to slightly opalescent and colorless to light yellow. The solution should not be used if discolored, or cloudy, or if foreign particles are present. Any leftover product remaining in the prefilled syringe or prefilled autoinjector should not be used. NOTE: The needle cover on the prefilled syringe as well as the prefilled syringe in the autoinjector contains dry natural rubber (a derivative of latex), which should not be handled by persons sensitive to latex.

Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard.

Dosage Forms and Strength

SmartJect™ Autoinjector

Each single dose SmartJect^TM autoinjector contains a prefilled glass syringe (27 gauge, ½ inch) providing 50 mg of SIMPONI^TM per 0.5 mL of solution.³⁰

The autoinjector’s design and safety features are shown in Figure 12.

**SmartJect^TM Autoinjector Features**

Sources: SIMPONI^TM prescribing information,³⁰ Centocor Ortho Biotech Inc.³⁶

Prefilled Syringe

Each single-dose, prefilled glass syringe (27 gauge, ½ inch) contains 50 mg of SIMPONI^TM per 0.5 mL of solution.³⁰ The design and safety features of the syringe are shown in Figure 13.

**SIMPONI^TM Prefilled Single-Dose Syringe**

Source: Centocor Ortho Biotech Inc.³⁶

HOW SUPPLIED/STORAGE AND HANDLING

Each SIMPONI^TM prefilled autoinjector or prefilled syringe is packaged in a light-blocking, cardboard outer carton. SIMPONI^TM is available in packs of one prefilled syringe (NDC 57894-070-01) or one prefilled SmartJect^TM autoinjector (NDC 57894-070-02).³⁰

Storage and stability. SIMPONI^TM must be refrigerated at 2°C to 8°C (36°F to 46°F) and protected from light. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Do not use SIMPONI^TM beyond the expiration date (EXP) on the carton or the expiration date on the prefilled syringe (observed through the viewing window) or the prefilled SmartJect^TM autoinjector.³⁰

Conclusion

SIMPONI^TM has been established as a safe and effective therapeutic option for treatment of moderately to severely active RA in adults, in combination with MTX. It also is indicated for active PsA in adults, alone or in combination with methotrexate, and for active AS in adults. SIMPONI^TM is an anti-TNF-α medication that can be administered by SC injection once monthly (Figure 14, page 27).

**Subcutaneous (SC) Anti-TNF Agents²¹–²⁴,³⁰**

*Indicated trademarks are the registered trademarks of their respective owners. ^†Dosing schedule presented is not inclusive of induction dosing.

This presentation is not intended to compare the relative safety, efficacy, or indications of these treatments. Please refer to each product's prescribing information for recommended dosing and administration.

When evaluating SIMPONI^TM for inclusion in a formulary, P&T committees must include consideration of the efficacy of this agent for multiple indications, safety issues, and acquisition and monitoring costs. Multiple clinical trials across the three indications have demonstrated that SIMPONI^TM is significantly more effective for the treatment of RA, PsA, and AS than placebo and that these improvements were sustained through 24 weeks. P&T committees may be able to develop a prescriptive protocol and identify patient populations for whom this drug will offer clinical benefit, based on a review of findings from the randomized controlled trials reviewed in this Product Profiler.

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PERMALINK

A Human Monoclonal Antibody Against Tumor Necrosis Factor-α

INTRODUCTION

DISEASE BACKGROUND

Rheumatoid Arthritis

FIGURE 1.

Ankylosing Spondylitis

Psoriatic Arthritis

PATHOPHYSIOLOGY

References

Description and Clinical Pharmacology

DESCRIPTION30

CLINICAL PHARMACOLOGY

Mechanism of Action30

Pharmacodynamics30

Pharmacokinetics30

Summary of Key Published Clinical Trials

RHEUMATOID ARTHRITIS

Golimumab, a Human Antibody to TNF-α Given by Monthly Subcutaneous Injections, in Active Rheumatoid Arthritis Despite Methotrexate Therapy: The GO-FORWARD Study

Methods and Trial Endpoints

FIGURE 2.

TABLE 1.

Results

TABLE 2.

FIGURE 3.

Safety Considerations

TABLE 3.

Golimumab in Patients With Active Rheumatoid Arthritis After Treatment With Tumor Necrosis Factor α Inhibitors (GO-AFTER Study): A Multi-centre, Randomised, Double-blind, Placebo-controlled, Phase III Trial

Methods and Trial Endpoints

FIGURE 4.

Results

TABLE 4.

FIGURE 5.

Safety Considerations

TABLE 5.

Golimumab, a Human Anti-Tumor Necrosis Factor α Monoclonal Antibody, Injected Subcutaneously Every Four Weeks in Methotrexate-Naïve Patients With Active Rheumatoid Arthritis [GO-BEFORE]

Methods and Trial Endpoints

FIGURE 6.

Results

TABLE 6.

FIGURE 7.

Safety Considerations

TABLE 7.

Golimumab, a New Human Tumor Necrosis Factor–α Antibody, Administered Every Four Weeks as a Subcutaneous Injection in Psoriatic Arthritis. Twenty-four-week efficacy and safety results of a randomized, placebo-controlled study [GO-REVEAL]

Methods and Endpoints

FIGURE 8.

Results

TABLE 8.

FIGURE 9.

Safety Considerations

TABLE 9.

ANKYLOSING SPONDYLITIS

Efficacy and Safety of Golimumab for Ankylosing Spondylitis: Results of a Randomized, Double-Blind, Placebo-Controlled, Phase III Trial [GO-RAISE]

Methods and Trial Endpoints

FIGURE 10.

Results

TABLE 10.

FIGURE 11.

Safety Considerations

TABLE 11.

P&T Committee Considerations

INDICATIONS AND USAGE30

Rheumatoid Arthritis

Psoriatic Arthritis

Ankylosing Spondylitis

EFFICACY

Clinical Studies

Rheumatoid Arthritis

Psoriatic Arthritis

Ankylosing Spondylitis

SAFETY

Contraindications30

Boxed Warnings30

Warnings and Precautions30

Serious Infections

Malignancies

Congestive Heart Failure

Demyelinating Disorders

Use with Abatacept and Anakinra

Use with Anakinra

DESCRIPTION³⁰

Mechanism of Action³⁰

Pharmacodynamics³⁰

Pharmacokinetics³⁰

INDICATIONS AND USAGE³⁰

Contraindications³⁰

Boxed Warnings³⁰

Warnings and Precautions³⁰

Adverse Reactions³⁰

Drug Interactions³⁰

Use in Specific Populations³⁰

Overdosage³⁰

Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis³⁰

Monitoring to Assess Safety³⁰

General Considerations for Administration³⁰