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Actemra

"The U.S. Food and Drug Administration today approved Actemra (tocilizumab), given alone or in combination with methotrexate, for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in children ages 2 years and older.

SJIA,"...

Actemra

Actemra

CLINICAL PHARMACOLOGY

Mechanism of Action

Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.

Pharmacodynamics

In clinical studies with the 4 mg per kg and 8 mg per kg IV doses or the 162 mg weekly and every other weekly SC doses of ACTEMRA, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg ACTEMRA. Pharmacodynamic changes were also observed to occur after ACTEMRA administration in PJIA and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known.

In healthy subjects administered ACTEMRA in doses from 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 to 5 days following ACTEMRA administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following ACTEMRA administration [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Rheumatoid Arthritis—Intravenous Administration

The pharmacokinetics characterized in healthy subjects and RA patients suggested that PK is similar between the two populations. The clearance (CL) of tocilizumab decreased with increased doses. At the 10 mg per kg single dose in RA patients, mean CL was 0.29 ± 0.10 mL per hr per kg and mean apparent terminal t1/2 was 151 ± 59 hours (6.3 days).

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis of 1793 rheumatoid arthritis patients treated with ACTEMRA 4 and 8 mg per kg every 4 weeks for 24 weeks.

The pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in area under the curve (AUC) and trough concentration (Cmin) was observed for doses of 4 and 8 mg per kg every 4 weeks. Maximum concentration (Cmax) increased dose-proportionally. At steady-state, estimated AUC and Cmin were 2.7 and 6.5-fold higher at 8 mg per kg as compared to 4 mg per kg, respectively. In a long-term study with dosing for 104 weeks, observed Cmin was sustained over time.

For doses of ACTEMRA 4 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 13000 ± 5800 mcg•h per mL, 1.49 ± 2.13 mcg per mL, and 88.3 ± 41.4 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 1.11 and 1.02, respectively. The accumulation ratio was higher for Cmin (1.96). Steady-state was reached following the first administration for Cmax and AUC, respectively, and after 16 weeks Cmin. For doses of ACTEMRA 8 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 35000 ± 15500 mcg•h per mL, 9.74 ± 10.5 mcg per mL, and 183 ± 85.6 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 1.22 and 1.06, respectively. The accumulation ratio was higher for Cmin (2.35). Steady-state was reached following the first administration and after 8 and 20 weeks for Cmax, AUC, and Cmin, respectively. Tocilizumab AUC, Cmin and Cmax increased with increase of body weight. At body weight at or above 100 kg, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 55500 ± 14100 mcg•h per mL, 19.0 ± 12.0 mcg per mL, and 269 ± 57 mcg per mL, respectively, which are higher than mean exposure values for the patient population. Therefore, ACTEMRA doses exceeding 800 mg per infusion are not recommended [see DOSAGE AND ADMINISTRATION].

Rheumatoid Arthritis—Subcutaneous Administration

The pharmacokinetics of tocilizumab was characterized using a population pharmacokinetic analysis using a database composed of 1759 rheumatoid arthritis patients treated with 162 mg SC every week, 162 mg SC every other week, and 8 mg/kg every 4 weeks for 24 weeks.

The pharmacokinetic parameters of tocilizumab did not change with time. For the 162 mg every week dose, the estimated mean (±SD) steady-state AUC1week, Cmin and Cmax of tocilizumab were 8200 ± 3600 mcg•h/mL, 44.6 ± 20.6 mcg/mL, and 50.9 ± 21.8 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.83, 6.37, and 5.47, respectively. Steady state was reached after 12 weeks for AUC, Cmin, and Cmax.

For the 162 mg every other week dose, the estimated mean (±SD) steady-state AUC2week, Cmin, and Cmax of tocilizumab were 3200 ± 2700 mcg•h/mL, 5.6 ± 7.0 mcg/mL, and 12.3 ± 8.7 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 5.6, and 2.12, respectively. Steady state was reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax.

Polyarticular Juvenile Idiopathic Arthritis—Intravenous Administration

The pharmacokinetics of tocilizumab was determined using a population pharmacokinetic analysis on a database composed of 188 patients with polyarticular juvenile idiopathic arthritis.

For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 29500 ± 8660 mcg•hr/mL, 182 ± 37 mcg/mL and 7.49 ± 8.2 mcg/mL, respectively.

For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 23200 ± 6100 mcg•hr/mL, 175 ± 32 mcg/mL and 2.35 ± 3.59 mcg/mL, respectively.

The accumulation ratios were 1.05 and 1.16 for AUC4weeks, and 1.43 and 2.22 for Cmin for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) doses, respectively. No accumulation for Cmax was observed.

Systemic Juvenile Idiopathic Arthritis—Intravenous Administration

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 75 patients with SJIA treated with 8 mg per kg (patients with a body weight at or above 30 kg) or 12 mg per kg (patients with a body weight less than 30 kg), given every 2 weeks. The estimated mean (± SD) AUC2 weeks, Cmax and Cmin of tocilizumab were 32200 ± 9960 mcg•hr per mL, 245 ± 57.2 mcg per mL and 57.5 ± 23.3 mcg per mL, respectively. The accumulation ratio for Cmin (week 12 over week 2) was 3.2 ± 1.3. Steady state was reached on or after week 12. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight.

Absorption

Following SC dosing in rheumatoid arthritis patients, the absorption half-life was around 4 days. The bioavailability for the SC formulation was 0.8.

Distribution

Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.

In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.

In pediatric patients with SJIA, the central volume of distribution was 0.94 L, the peripheral volume of distribution was 1.60 L resulting in a volume of distribution at steady state of 2.54 L.

Elimination

The total clearance of tocilizumab is concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA, 5.8 mL per h in pediatric patients with PJIA, and 7.1 mL per h in pediatric patients with SJIA. The concentration-dependent nonlinear clearance plays a major role at low tocilizumab concentrations. Once the nonlinear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.

The t1/2 of tocilizumab is concentration-dependent. For IV administration, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For SC administration, the concentration-dependent apparent t1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.

The t1/2 of tocilizumab in children with PJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight less than 30 kg) during a dosing interval at steady state.

The t1/2 of tocilizumab in pediatric patients with SJIA is up to 23 days for the two body weight categories at week 12.

Pharmacokinetics in Special Populations

Population pharmacokinetic analyses in adult rheumatoid arthritis patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. The body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose SC regimens.

Hepatic Impairment

No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.

Renal Impairment

No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted.

Most of the RA patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault) did not impact the pharmacokinetics of tocilizumab. No dose adjustment is required in patients with mild renal impairment.

Drug Interactions

In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of ACTEMRA, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when ACTEMRA is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates) [see DRUG INTERACTIONS].

Simvastatin

Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with ACTEMRA, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of ACTEMRA in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of ACTEMRA (due to normalization of CYP3A4) or higher exposures after discontinuation of ACTEMRA.

Omeprazole

Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after ACTEMRA infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects.

Dextromethorphan

Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of ACTEMRA (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after ACTEMRA infusion.

Clinical Studies

Rheumatoid Arthritis –Intravenous Administration

The efficacy and safety of intravenously administered ACTEMRA was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. ACTEMRA was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V).

Study I evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were MTX-na´ve, and over 40% of patients had rheumatoid arthritis less than 2 years. Patients received ACTEMRA 8 mg per kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of ACTEMRA patients who achieved an ACR 20 response at Week 24.

Study II was a 104-week study with an ongoing optional 156-week extension phase that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received ACTEMRA 8 mg per kg, ACTEMRA 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with ACTEMRA 8 mg per kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a greater than 70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score.

Study III evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received ACTEMRA 8 mg per kg, ACTEMRA 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24.

Study IV evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received ACTEMRA 8 mg per kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24.

Study V evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received ACTEMRA 8 mg per kg, ACTEMRA 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20response at week 24.

Clinical Response

The percentages of intravenous ACTEMRA-treated patients achieving ACR 20, 50 and 70 responses are shown in Table 3. In all intravenous studies, patients treated with 8 mg per kg ACTEMRA had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo-treated patients at week 24.

During the 24 week controlled portions of Studies I to V, patients treated with ACTEMRA at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with ACTEMRA 8 mg per kg.

Table 3 : Clinical Response at Weeks 24 and 52 in Active and Placebo Controlled Trials of Intravenous ACTEMRA (Percent of Patients)

  Percent of Patients
Study I Study II Study III Study IV Study V
MTX
N=284
ACTEMRA 8 mg per kg
N=286
(95% CI)a
Placebo +MTX
N=393
ACTEMRA 4 mg per kg + MTX
N=399
( 95% CI)a
ACTEMRA 8 mg per kg + MTX
N=398
(95% CI)a
Placebo +MTX
N=204
ACTEMRA 4 mg per kg + MTX
N=213
(95% CI)a
ACTEMRA 8 mg per kg + MTX
N=205
(95% CI)a
Placebo + DMARDs
N=413
ACTEMRA 8 mg per kg + DMARDs
N=803
(95% CI)a
Placebo +MTX
N=158
ACTEMRA 4 mg per kg + MTX
N=161
(95% CI)a
ACTEMRA 8 mg per kg + MTX
N=170
(95% CI)a
Response Rate
ACR 20
  Week 24 53% 70% 27% 51% 56% 27% 48% 59% 24% 61% 10% 30% 50%
  Week 52 N/A (0.11, 0.27) N/A 25% (0.17, 0.29) 47% (0.15, 0.28) (0.23, 0.35) 56% (0.25, 0.38) N/A (0.15, 0.32) N/A (0.23, 0.41) N/A N/A (0.30, 0.40) N/A N/A (0.15, 0.36) N/A (0.36, 0.56) N/A
ACR 50
  Week 24 34% 44% 10% 25% 32% 11% 32% 44% 9% 38% 4% 17% 29%
  Week 52 N/A (0.04, 0.20) N/A 10% (0.09, 0.20) 29% (0.14, 0.25) (0.16, 0.28) 36% (0.21, 0.32) N/A (0.13, 0.29) N/A (0.25, 0.41) N/A N/A (0.23, 0.33) N/A N/A (0.05, 0.25) N/A (0.21, 0.41) N/A
ACR 70
  Week 24 15% 28% 2% 11% 13% 2% 12% 22% 3% 21% 1% 5% 12%
  Week 52 N/A (0.07, 0.22) N/A 4% (0.03, 0.13) 16% (0.08, 0.17) (0.05, 0.15) 20% (0.12, 0.21) N/A (0.04, 0.18) N/A (0.12, 0.27) N/A N/A (0.13, 0.21) N/A N/A (-0.06, 0.14) N/A (0.03, 0.22) N/A
Major Clinical Responsesb
  Week 52 N/A N/A 1% 4% (0.01, 0.06) 7% (0.03, 0.09) N/A N/A N/A N/A N/A N/A N/A N/A
aCI: 95% confidence interval of the weighted difference to placebo adjusted for site (and disease duration for Study I only)
bMajor clinical response is defined as achieving an ACR 70 response for a continuous 24 week period

In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg ACTEMRA + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo +MTX treated patients at week 52. The proportion of ACTEMRA-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in Table 4.

Table 4 : Proportion of Patients with DAS28-ESR Less Than 2.6 with Number of Residual Active Joints in Trials of Intravenous ACTEMRA

  Study II
Placebo + MTX
N = 393
ACTEMRA 4 mg per kg + MTX
N = 399
ACTEMRA 8 mg per kg + MTX
N = 398
DAS28-ESR less than 2.6
Proportion of responders at week 52 (n)
95% confidence interval
3% (12) 18% (70)
0.10, 0.19
32% (127)
0.24, 0.34
Of responders, proportion with 0 active joints (n) 33% (4) 27% (19) 21% (27)
Of responders, proportion with 1 active joint (n) 8% (1) 19% (13) 13% (16)
Of responders, proportion with 2 active joints (n) 25% (3) 13% (9) 20% (25)
Of responders, proportion with 3 or more active joints (n) 33% (4) 41% (29) 47% (59)
*n denotes numerator of all the percentage. Denominator is the intent-to-treat population. Not all patients received DAS28 assessments at Week 52.

The results of the components of the ACR response criteria for Studies III and V are shown in Table 5. Similar results to Study III were observed in Studies I, II and IV.

Table 5 : Components of ACR Response at Week 24 in Trials of Intravenous ACTEMRA

Component (mean) Study III Study V
ACTEMRA 4 mg per kg + MTX
N=213
ACTEMRA 8 mg per kg + MTX
N=205
Placebo + MTX
N=204
ACTEMRA 4 mg per kg + MTX
N=161
ACTEMRA 8 mg per kg + MTX
N=170
Placebo + MTX
N=158
Baseline Week 24a Baseline Week 24 a Baseline Week 24 Baseline Week 24 a Baseline Week 24 a Baseline Week 24
Number of tender joints (0-68) 33 19 -7.0 (-10.0, -4.1) 32 14.5 -9.6 (-12.6, -6.7) 33 25 31 21 -10.8 (-14.6, -7.1) 32 17 -15.1 (-18.8, -11.4) 30 30
Number of swollen joints (0-66) 20 10 -4.2 (-6.1, -2.3) 19.5 8 -6.2 (-8.1, -4.2) 21 15 19.5 13 -6.2 (-9.0, -3.5) 19 11 -7.2 (-9.9, -4.5) 19 18
Painb 61 33 -11.0 (-17.0, -5.0) 60 30 -15.8 (-21.7, -9.9) 57 43 63.5 43 -12.4 (-22.1, -2.1) 65 33 -23.9 (-33.7, -14.1) 64 48
Patient global assessmentb 66 34 -10.9 (-17.1, -4.8) 65 31 -14.9 (-20.9, -8.9) 64 45 70 46 -10.0 (-20.3, 0.3) 70 36 -17.4 (-27.8, -7.0) 71 51
Physician global assessmentb 64 26 -5.6 (-10.5, -0.8) 64 23 -9.0 (-13.8, -4.2) 64 32 66.5 39 -10.5 (-18.6, -2.5) 66 28 -18.2 (-26.3, -10.0) 67.5 43
Disability index (HAQ)c 1.64 1.01 -0.18 (-0.34, -0.02) 1.55 0.96 -0.21 (-0.37, -0.05) 1.55 1.21 1.67 1.39 -0.25 (-0.42, -0.09) 1.75 1.34 -0.34 (-0.51, -0.17) 1.7 1.58
CRP (mg per dL) 2.79 1.17 -1.30 (-2.0, -0.59) 2.61 0.25 -2.156 (-2.86, -1.46) 2.36 1.89 3.11 1.77 -1.34 (-2.5, -0.15) 2.8 0.28 -2.52 (-3.72, -1.32) 3.705 3.06
aData shown is mean at week 24, difference in adjusted mean change from baseline compared with placebo + MTX at week 24 and 95% confidence interval for that difference
bVisual analog scale: 0 = best, 100 = worst
cHealth Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities

The percent of ACR 20 responders by visit for Study III is shown in Figure 1. Similar response curves were observed in studies I, II, IV, and V.

Figure 1 : Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX)*

Percent of ACR 20 Responders by Visit for Study III - Illustration

*The same patients may not have responded at each timepoint.

Radiographic Response

In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in Table 6. ACTEMRA 4 mg per kg slowed (less than 75% inhibition compared to the control group) and ACTEMRA 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52.

Table 6 : Mean Radiographic Change from Baseline to Week 52 in Study II

  Placebo + MTX
N=294
ACTEMRA 4 mg per kg + MTX
N=343
ACTEMRA 8 mg per kg + MTX
N=353
Week 52*
Total Sharp-Genant Score, Mean (SD) 1.17
(3.14)
0.33
(1.30)
0.25
(0.98)
  Adjusted Mean difference**
(95%CI)
  -0.83
(-1.13, -0.52)
-0.90
(-1.20, -0.59)
Erosion Score, Mean (SD) 0.76
(2.14)
0.20
(0.83)
0.15
(0.77)
  Adjusted Mean difference**
(95%CI)
  -0.55
(-0.76, -0.34)
-0.60
(-0.80, -0.39)
Joint Space Narrowing Score, Mean (SD) 0.41
(1.71)
0.13
(0.72)
0.10
(0.49)
  Adjusted Mean difference**
(95%CI)
  -0.28
(-0.44, -0.11)
-0.30
(-0.46, -0.14)
* Week 52 analysis employs linearly extrapolated data for patients after escape, withdrawal, or loss to follow up.
** Difference between the adjusted means (ACTEMRA + MTX - Placebo + MTX)
SD = standard deviation

The mean change from baseline to week 104 in Total Sharp-Genant Score for the ACTEMRA 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group.

In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the ACTEMRA 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to ACTEMRA 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients.

Health Related Outcomes

In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of ACTEMRA demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for ACTEMRA 8 mg per kg, ACTEMRA 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the ACTEMRA 8 mg per kg and ACTEMRA 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group.

Rheumatoid Arthritis–Subcutaneous Administration

The efficacy and safety of subcutaneously administered ACTEMRA was assessed in two double-blind, controlled, multicenter studies in patients with active RA. One study (SC-I) was a non-inferiority study that compared the efficacy and safety of ACTEMRA 162 mg administered every week subcutaneously (SC) to 8 mg per kg intravenously every four weeks. The second study (SC-II) was a placebo controlled superiority study that evaluated the safety and efficacy of ACTEMRA 162 mg administered every other week SC to placebo. Both SC-I and SC-II required patients to be > 18 years of age with moderate to severe active rheumatoid arthritis diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline (SC-I) or at least 8 tender and 6 swollen joints at baseline (SC-II), and an inadequate response to their existing DMARD therapy, where approximately 20% also had a history of inadequate response to at least one TNF inhibitor. All patients in both SC studies received background non-biologic DMARD(s).

In SC-I, 1262 patients were randomized 1:1 to receive ACTEMRA SC 162 mg every week or ACTEMRA intravenous 8 mg/kg every four weeks in combination with DMARD(s). In SC-II, 656 patients were randomized 2:1 to ACTEMRA SC 162 mg every other week or placebo, in combination with DMARD(s). The primary endpoint in both studies was the proportion of patients who achieved an ACR20 response at Week 24.

The clinical response to 24 weeks of ACTEMRA SC therapy is shown in Table 7. In SC-I, the primary outcome measure was ACR20 at Week 24. The pre-specified non-inferiority margin was a treatment difference of 12%. The study demonstrated non-inferiority of ACTEMRA with respect to ACR20 at Week 24; ACR50, ACR70, and DAS28 responses are also shown in Table 7. In SC-II, a greater portion of patients treated with ACTEMRA 162 mg SC every other week achieved ACR20, ACR50, and ACR70 responses compared to placebo-treated patients (Table 7). Further, a greater proportion of patients treated with ACTEMRA 162 mg SC every other week achieved a low level of disease activity as measured by a DAS28-ESR less than 2.6 at Week 24 compared to those treated with placebo (Table 7).

Table 7 : Clinical Response at Week 24 in Trials of Subcutaneous ACTEMRA (Percent of Patients)

  SC-Ia SC-IIb
TCZ SC 162 mg every week + DMARD
N=558
TCZ IV 8mg/kg + DMARD
N=537
TCZ SC 162 mg every other week + DMARD
N=437
Placebo + DMARD
N=219
ACR20
  Week 24 69% 73.40% 61% 32%
  Weighted difference (95% CI) -4% (-9.2, 1.2) 30% (22.0, 37.0)
ACR50
  Week 24 47% 49% 40% 12%
  Weighted difference (95% CI) -2% (-7.5, 4.0) 28% (21.5, 34.4)
ACR70
  Week 24 24% 28% 20% 5%
  Weighted difference (95% CI) -4% (-9.0, 1.3) 15% (9.8, 19.9)
Change in DAS28 [Adjusted mean]
  Week 24 -3.5 -3.5 -3.1 -1.7
  Adjusted mean difference (95% CI) 0 (-0.2, 0.1) -1.4 (-1.7; -1.1)
DAS28 < 2.6
  Week 24   38.40% 36.90% 32.00% 4.00%
  Weighted difference (95% CI) 0.9 (-5.0, 6.8) 28.6 (22.0, 35.2)
TCZ = tocilizumab
aPer Protocol Population
bIntent To Treat Population

The results of the components of the ACR response criteria and the percent of ACR20 responders by visit for ACTEMRA-SC in Studies SC-I and SC-II were consistent with those observed for ACTEMRA-IV.

Radiographic Response

In study SC-II, the progression of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified total Sharp score (mTSS). At week 24, significantly less radiographic progression was observed in patients receiving ACTEMRA SC every other week plus DMARD(s) compared to placebo plus DMARD(s); mean change from baseline in mTSS of 0.62 vs. 1.23, respectively, with an adjusted mean difference of -0.60 (-1.1, -0.1). These results are consistent with those observed in patients treated with intravenous ACTEMRA.

Health Related Outcomes

In studies SC-I and SC-II, the mean decrease from baseline to week 24 in HAQ-DI was 0.6, 0.6, 0.4 and 0.3, and the proportion of patients who achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) was 65%, 67%, 58% and 47%, for the SC every week, IV 8 mg/kg, SC every other week, and placebo treatment groups, respectively.

Polyarticular Juvenile Idiopathic Arthritis-Intravenous Administration

The efficacy of ACTEMRA was assessed in a three-part study including an open-label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e.g., TNF antagonists or T cell costimulation modulator) were not permitted in the study.

Part I consisted of a 16-week active ACTEMRA treatment lead-in period (n=188) followed by Part II, a 24week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received ACTEMRA at 8 mg/kg IV once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either ACTEMRA 8 mg/kg or 10 mg/kg IV every four weeks. At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy.

In Part II, patients (ITT, n=163) were randomized to ACTEMRA (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape.

The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16.

ACTEMRA treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%).

During the withdrawal phase (Part II), more patients treated with ACTEMRA showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo.

Systemic Juvenile Idiopathic Arthritis-Intravenous Administration

The efficacy of ACTEMRA for the treatment of active SJIA was assessed in a 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (ACTEMRA:placebo = 2:1) to one of two treatment groups: 75 patients received ACTEMRA infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with ACTEMRA in the open-label extension phase at weight appropriate dosing.

The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ).

Primary endpoint result and JIA ACR response rates at Week 12 are shown in Table 8.

Table 8 : Efficacy Findings at Week 12

  ACTEMRA
N=75
Placebo
N=37
Primary Endpoint: JIA ACR 30 response + absence of fever
Responders 85% 24%
Weighted difference (95% CI) 62 (45, 78) -
JIA ACR Response Rates at Week 12
JIA ACR 30
Responders 91% 24%
Weighted differencea (95% CI)b 67 (51, 83) -
JIA ACR 50
Responders 85% 11%
Weighted differencea (95% CI) b 74 (58, 90) -
JIA ACR 70
Responders 71% 8%
Weighted differencea (95% CI) b 63 (46, 80) -
aThe weighted difference is the difference between the ACTEMRA and Placebo response rates, adjusted for the stratification factors (weight, disease duration, background oral corticosteroid dose and background methotrexate use).
bCI: confidence interval of the weighted difference.

The treatment effect of ACTEMRA was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks).

Systemic Features

Of patients with fever or rash at baseline, those treated with ACTEMRA had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks).

Corticosteroid Tapering

Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), ACTEMRA patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction.

Seventeen (24%) ACTEMRA patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) ACTEMRA patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more.

Health Related Outcomes

Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the ACTEMRA treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group.

Last reviewed on RxList: 11/4/2013
This monograph has been modified to include the generic and brand name in many instances.

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