Actemra (tocilizumab) – 7 indications

Scroll down for information on each indication:

• Rheumatoid arthritis; approved 01/01/2010
• Systemic juvenile idiopathic arthritis; approved 04/01/2011
• Polyarticular Juvenile Idiopathic Arthritis; approved 05/01/2013
• Giant cell arteritis; approved 05/01/2017
• CAR T-cell induced Cytokine Release Syndrome; approved 09/01/2017
• Systemic sclerosis-associated interstitial lung disease; approved 03/01/2021
• COVID-19 in hospitalized adult patients; approved 12//21/2022

General Information

 Actemra (tocilizumab) is an interleukin-6 (IL-6) receptor antagonist.

Actemra is specifically indicated for the following conditions:

• Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).
• Patients 2 years of age and older with active systemic juvenile idiopathic arthritis.
• Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis.
• Adult patients with giant cell arteritis.
• Adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome.
• To slow the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).
• For the treatment of COVID-19 in hospitalized adult patients who are receiving systemic corticosteroids and require supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

Mechanism of Action

Actemra (tocilizumab) binds 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.

Side Effects

Adverse effects associated with the use of Actemra may include, but are not limited to, the following:

• upper respiratory tract infections
• nasopharyngitis
• headache
• hypertension
• increased ALT
• injection site reaction

The Actemra drug label comes with the following Black Box Warning: Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving Actemra. If a serious infection develops, interrupt Actemra until the infection is controlled. Perform test for latent TB; if positive, start treatment for TB prior to starting Actemra. Monitor all patients for active TB during treatment, even if initial latent TB test is negative.

Indication 1 - rheumatoid arthritis 

Approved 01/01/2010

Dosing/Administration

Recommended Adult Intravenous Dosage:

When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

Recommended Adult Subcutaneous Dosage:

• Patients less than 100 kg weight: 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
• Patients at or above 100 kg weight: 162 mg administered subcutaneously every week

Clinical Trial Results

The FDA approval of Actemra for adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs was based on five randomized, double-blind, multicenter studies. Actemra was administered 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 One
This study evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 6 months prior to randomization, or who had not discontinued previous MTX treatment. The subjects received Actemra 8 mg/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 ACR20 response at Week 24. ACR20 was reached by 70% of the Actemra arm vs. 53% of the MTX alone arm.
Study Two
This ongoing 2-year study with a planned interim analysis at week 24 evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Actemra 8 mg/kg, Actemra 4 mg/kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint at week 24 was the proportion of patients who achieved an ACR20 response. ACR20 was reached by 27% in the placebo/MTX arm, 51% in the Actemra 4mg/MTX arm and 56% in the Actemra 8 mg/MTX arm.
Study Three
This trial evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Actemra 8 mg/kg, Actemra 4 mg/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 ACR20 response at week 24. ACR20 was reached by 27% of the placebo/MTX arm, 48% of the Actemra 4mg/MTX arm and 59% of the Actemra 8 mg/MTX arm.
Study Four
This study evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received Actemra 8 mg/kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24. ACR20 was reached by 25% of the placebo/DMARDS arm and 61% of the Actemra/DMARDS arm.
Study Five
This study 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/kg, Actemra 4 mg/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 ACR20 response at week 24. ACR20 was reached by 10% of the placebo/MTX arm, 30% of the Actrmea 4mg/MTX arm and 50% of the Actemra 8 mg/MTX arm.

Indication 2 - Systemic juvenile idiopathic arthritis (SJIA)

Approved 04/01/2011

Dosing/Administration

Recommended Intravenous SJIA Dosage Every 2 Weeks

• Patients less than 30 kg weight :12 mg per kg
• Patients at or above 30 kg weight: 8 mg per kg

Recommended Subcutaneous SJIA Dosage

• Patients less than 30 kg weight: 162 mg every two weeks
• Patients at or above 30 kg weight 162 mg every week

Clinical Trial Results

The FDA approval of Actemra for systemic juvenile idiopathic arthritis was based on a 12-week randomized, double blind, placebo-controlled, parallel group, two-arm study. The subjects (n=75) 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 or placebo infusions every two weeks (n=37). The primary endpoint was the proportion of subjects with at least 30% improvement in JIA ACR core set (JIA ACR30 response) at Week 12 and absence of fever. The primary endpoint was reached by 85% of the Actemra arm and 24% of the placebo arm. Secondary endpoints, including JIA ACR 50 and JIA ACR 70 were also reached.

Indication 3 - Polyarticular Juvenile Idiopathic Arthritis (PJIA)

Approved 05/01/2013

Dosing/Administration

Recommended Intravenous PJIA Dosage Every 4 Weeks

• Patients less than 30 kg weight: 10 mg per kg
• Patients at or above 30 kg weight: 8 mg per kg

Recommended Subcutaneous PJIA Dosage

• Patients less than 30 kg weight: 162 mg once every three weeks
• Patients at or above 30 kg weight: 162 mg once every two weeks

Clinical Trial Results

The FDA approval of Actemra for polyarticular juvenile idiopathic arthritis (PJIA) was based on CHERISH, a phase III trial. The trial consisted of an open label phase, followed by a randomized double-blind placebo-controlled withdrawal phase. The study demonstrated that subjects treated with Actemra experienced clinically meaningful improvement in signs and symptoms of PJIA. A total of 91% of subjects taking Actemra plus MTX and 83% taking Actemra alone achieved an ACR 30 response at week 16 compared to baseline. In the randomized double-blind placebo-controlled withdrawal phase of the trial, Actemra-treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% vs. 48%).

Indication 4 - Giant cell arteritis (GCA)

Approved 05/01/2017

Dosing/Administration

The recommended dose of Actemra for adult patients with GCA is 162 mg given once every week as a subcutaneous injection, in combination with a tapering course of glucocorticoids. A dose of 162 mg given once every other week as a subcutaneous injection, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations. Actemra can be used alone following discontinuation of glucocorticoids. 

Clinical Trial Results

The FDA approval of Actemra for adults with GCA was based on a single, randomized, double-blind, multicenter study in patients (n=251) with new-onset or relapsing GCA who were randomized to one of four treatment arms. Two subcutaneous doses of Actemra (162 mg every week and 162 mg every other week) were compared to two different placebo control groups (pre-specified prednisone-taper regimen over 26 weeks and 52 weeks) randomized 2:1:1:1. The study consisted of a 52-week blinded period, followed by a 104-week open-label extension. All patients received background glucocorticoid (prednisone) therapy. Each of the Actemra-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen with the aim to reach 0 mg by 52 weeks designed to be more in keeping with standard practice. 40 The primary efficacy endpoint was the proportion of patients achieving sustained remission from Week 12 through Week 52. Actemra 162 mg weekly and 162 mg every other week + 26 weeks prednisone taper both showed superiority in achieving sustained remission from Week 12 through Week 52 compared with placebo + 26 weeks prednisone taper. Both Actemra treatment arms also showed superiority compared to the placebo + 52 weeks prednisone taper.

Indication 5 - (CAR) T cell-induced severe or life-threatening cytokine release syndrome

Approved 09/01/2017

Dosage/Administration

Actemra for the treatment of (CAR) T cell-induced CRS is administered intravenously, either alone or in combination with corticosteroids.

The recommended dose for patients less than 30 kg weight is 12 mg per kg

The recommended dose for patients at or above 30 kg weight is  8 mg per kg 

Clinical Trial Results

The FDA approval of Actemra for adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome was based on a retrospective analysis of pooled outcome data from clinical trials of CAR T cell therapies for blood cancers, which assessed the efficacy of Actemra in the treatment of CRS. The study population included 45 pediatric and adult patients treated with Actemra, with or without additional high-dose corticosteroids, for severe or life-threatening CRS. Thirty-one patients (69%; 95% CI: 53%–82%) achieved a response, defined as resolution of CRS within 14 days of the first dose of Actemra, no more than two doses of Actemra were needed, and no drugs other than Actemra and corticosteroids were used for treatment. No adverse reactions related to Actemra were reported. A second study confirmed resolution of CRS within 14 days using an independent cohort that included 15 patients with CAR T cell-induced CRS.

Indication 6 - systemic sclerosis-associated interstitial lung disease (SSc-ILD)

Approved 03/01/2021

Dosing/Administration

The recommended dose of Actemra for patients with SSc-ILD is 162 mg given once every week as a subcutaneous injection.

Clinical Trial Results

The FDA approval of Actemra for SSc-ILD was based on data from the focuSSced trial, a Phase III randomized, double-blind, placebo-controlled clinical trial of 212 adults with systemic sclerosis. Supportive information was also used from the faSScinate trial, a Phase II/III, randomized, double-blind, placebo-controlled study in patients with SSc. There was not a statistically significant effect on the primary endpoint of mRSS in the faSScinate trial.

The focuSSced trial did not meet its primary endpoint of change from baseline to week 48 in the modified Rodnan Skin Score (mRSS), which is a standard outcome measure for skin fibrosis (the scarring or hardening of the skin) in SSc. However, in the overall population of the focuSSced study, patients treated with Actemra, as compared to placebo-treated patients, were observed to have less decline from baseline to week 48 in observed forced vital capacity (FVC), a common measure of lung function that assesses how much air can be exhaled, and percent predicted forced vital capacity (ppFVC), which compares the observed FVC to that expected for a healthy person of the same age, gender, race and height. FVC results were similar in the faSScinate study.

Of the 212 patients who were randomized into the focuSSced study, 68 patients (65%) in the Actemra arm and 68 patients (64%) in the placebo arm had SSc-ILD at baseline, as confirmed by a visual read of high resolution computed tomograph (HRCT) by blinded thoracic radiologists. Post-hoc exploratory analyses were performed to evaluate the results within the subgroups of patients with and without SSc-ILD. The ppFVC and FVC results in the overall population were primarily driven by results in the SSc-ILD subgroup. In that subgroup, patients in the Actemra group had a smaller decline in mean ppFVC than patients on placebo (0.07% vs. -6.4%, mean difference 6.47%), and a smaller decline in FVC compared to placebo (mean change -14 mL vs. -255 mL, mean difference 241 mL). The mean change from baseline to week 48 in mRSS in patients receiving Actemra compared to placebo was -5.88 vs. -3.77, mean difference -2.11.

Indication 7 - for the treatment of COVID-19 in hospitalized adult patients

Approved 21/21/22

Four randomized, controlled studies evaluated Actemra for the treatment of COVID-19 in more than 5,500 hospitalized patients. Altogether, the results of these four studies (the University of Oxford-led RECOVERY trial, along with the Genentech-sponsored global trials, EMPACTA, COVACTA and REMDACTA) showed that Actemra may improve outcomes in patients receiving corticosteroids and requiring supplemental oxygen or breathing support.