ACTEMRA (Page 10 of 15)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as tocilizumab, is presently unknown.

Fertility and reproductive performance were unaffected in male and female mice that received a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days.

14 CLINICAL STUDIES

14.1 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 (NCT00109408) 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-naïve, 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 (NCT00106535) was a 104-week study with an 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 (NCT00106548) 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 (NCT00106574) 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 (NCT00106522) 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 20 response 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
Response RateStudy IStudy IIStudy IIIStudy IVStudy V
MTXACTEMRA 8 mg per kgPlacebo + MTXACTEMRA 4 mg per kg + MTXACTEMRA 8 mg per kg + MTXPlacebo + MTXACTEMRA 4 mg per kg + MTXACTEMRA 8 mg per kg + MTXPlacebo + DMARDsACTEMRA 8 mg per kg + DMARDsPlacebo + MTXACTEMRA 4 mg per kg + MTXACTEMRA 8 mg per kg + MTX
N=284N=286N=393N=399N=398N=204N=213N=205N=413N=803N=158N=161N=170
(95% CI)*( 95% CI)*(95% CI)*( 95% CI)*(95% CI)*(95% CI)*( 95% CI)*(95% CI)*
*
CI: 95% confidence interval of the weighted difference to placebo adjusted for site (and disease duration for Study I only)
Major clinical response is defined as achieving an ACR 70 response for a continuous 24 week period
ACR 20
Week 2453%70%(0.11, 0.27)27%51%(0.17, 0.29)56%(0.23, 0.35)27%48%(0.15, 0.32)59%(0.23, 0.41)24%61%(0.30, 0.40)10%30%(0.15, 0.36)50%(0.36, 0.56)
Week 52N/AN/A25%47%(0.15, 0.28)56%(0.25, 0.38)N/AN/AN/AN/AN/AN/AN/AN/A
ACR 50
Week 2434%44%(0.04, 0.20)10%25%(0.09, 0.20)32%(0.16, 0.28)11%32%(0.13, 0.29)44%(0.25, 0.41)9%38%(0.23, 0.33)4%17%(0.05, 0.25)29%(0.21, 0.41)
Week 52N/AN/A10%29%(0.14, 0.25)36%(0.21, 0.32)N/AN/AN/AN/AN/AN/AN/AN/A
ACR 70
Week 2415%28%(0.07, 0.22)2%11%(0.03, 0.13)13%(0.05, 0.15)2%12%(0.04, 0.18)22%(0.12, 0.27)3%21%(0.13, 0.21)1%5%(-0.06, 0.14)12%(0.03, 0.22)
Week 52N/AN/A4%16%(0.08, 0.17)20%(0.12, 0.21)N/AN/AN/AN/AN/AN/AN/AN/A
Major Clinical Responses
Week 52N/AN/A1%4%(0.01, 0.06)7%(0.03, 0.09)N/AN/AN/AN/AN/AN/AN/AN/A

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 + MTXN = 393ACTEMRA 4 mg per kg + MTXN = 399ACTEMRA 8 mg per kg + MTXN = 398
*n denotes numerator of all the percentage. Denominator is the intent-to-treat population. Not all patients received DAS28 assessments at Week 52.
DAS28-ESR less than 2.6
Proportion of responders at week 52 (n)95% confidence interval3% (12)18% (70)0.10, 0.1932% (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)

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
Study IIIStudy V
ACTEMRA 4 mg per kg + MTXACTEMRA 8 mg per kg + MTXPlacebo + MTXACTEMRA 4 mg per kg + MTXACTEMRA 8 mg per kg + MTXPlacebo + MTX
N=213N=205N=204N=161N=170N=158
Component (mean)BaselineWeek 24*BaselineWeek 24*BaselineWeek 24BaselineWeek 24*BaselineWeek 24*BaselineWeek 24
*
Data 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
Visual analog scale: 0 = best, 100 = worst
Health Assessment Questionnaire: 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities
Number of tender joints (0-68)3319-7.0(-10.0, -4.1)3214.5-9.6(-12.6, -6.7)33253121-10.8(-14.6, -7.1)3217-15.1(-18.8, -11.4)3030
Number of swollen joints (0-66)2010-4.2(-6.1, -2.3)19.58-6.2(-8.1, -4.2)211519.513-6.2(-9.0, -3.5)1911-7.2(-9.9, -4.5)1918
Pain 6133-11.0(-17.0, -5.0)6030-15.8(-21.7, -9.9)574363.543-12.4(-22.1, -2.1)6533-23.9(-33.7, -14.1)6448
Patient global assessment 6634-10.9(-17.1, -4.8)6531-14.9(-20.9, -8.9)64457046-10.0(-20.3, 0.3)7036-17.4(-27.8, -7.0)7151
Physician global assessment 6426-5.6(-10.5, -0.8)6423-9.0(-13.8, -4.2)643266.539-10.5(-18.6, -2.5)6628-18.2(-26.3, -10.0)67.543
Disability index (HAQ)1.641.01-0.18(-0.34, -0.02)1.550.96-0.21(-0.37, -0.05)1.551.211.671.39-0.25(-0.42, -0.09)1.751.34-0.34(-0.51, -0.17)1.701.58
CRP (mg per dL)2.791.17-1.30(-2.0, -0.59)2.610.25-2.156(-2.86, -1.46)2.361.893.111.77-1.34(-2.5, -0.15)2.800.28-2.52(-3.72, -1.32)3.7053.06

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.

*
The same patients may not have responded at each timepoint.
Figure 1 Percent of ACR 20 Responders by Visit for Study III (Inadequate Response to MTX)*
Figure 1
(click image for full-size original)

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 ACTEMRA 4 mg per kg + MTX ACTEMRA 8 mg per kg + MTX
N=294 N=343 N=353
SD = standard deviation
*
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)
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)

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.

Other Health-Related Outcomes

General health status was assessed by the Short Form Health Survey (SF-36) in Studies I – V. Patients receiving ACTEMRA demonstrated greater improvement from baseline compared to placebo in the Physical Component Summary (PCS), Mental Component Summary (MCS), and in all 8 domains of the SF-36.

Cardiovascular Outcomes

Study WA25204 (NCT01331837) was a randomized, open-label (sponsor-blinded), 2-arm parallel-group, multi-center, non-inferiority, cardiovascular (CV) outcomes trial in patients with a diagnosis of moderate to severe RA. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with ACTEMRA compared with a TNF inhibitor standard of care (etanercept).

The study included 3,080 seropositive RA patients with active disease and an inadequate response to non-biologic disease-modifying anti-rheumatic drugs, who were aged ≥50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV ACTEMRA 8 mg/kg Q4W or SC etanercept 50 mg QW and followed for an average of 3.2 years. The primary endpoint was the comparison of the time-to-first occurrence of any component of a composite of major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke, or CV death), with the final intent-to-treat analysis based on a total of 161 confirmed CV events (83/1538 [5.4%] for ACTEMRA; 78/1542 [5.1%] for etanercept) reviewed by an independent and blinded adjudication committee.

Non-inferiority of ACTEMRA to etanercept for cardiovascular risk was determined by excluding >80% relative increase in the risk of MACE. The estimated hazard ratio (HR) for the risk of MACE comparing ACTEMRA to etanercept was 1.05; 95% CI (0.77, 1.43).

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