Actemra (tocilizumab)

Actemra (tocilizumab) is an interleukin-6 (IL-6) receptor inhibitor used to treat adults with moderate-to-severe rheumatoid arthritis (RA) who have not adequately responded to or cannot tolerate other approved drug classes for treating rheumatoid arthritis. The drug is a humanized monoclonal antibody that works by blocking the action of IL-6, an immune system protein that is overabundant in people with RA. Tocilizumab is approved for once-a-month intravenous (IV) administration in physicians’ offices, hospitals, and infusion centers, and may be used alone or in combination with methotrexate or other disease-modifying antirheumatic drugs (DMARDs).

The recommended starting dose for tocilizumab is 4 mg/kg when used in combination with DMARDs or as a monotherapy in patients who have had an inadequate response to ≥1 tumor necrosis factor (TNF) antagonists; the dose may then be increased to 8 mg/kg based on clinical response.

The recommended use of tocilizumab is limited to patients who have failed other approved therapies because of serious safety concerns that were noted in clinical studies. These safety concerns include elevated liver enzymes, elevated low-density lipoprotein cholesterol (LDL-C), hypertension, and gastrointestinal perforations.

The efficacy and safety of tocilizumab was determined in 5 clinical trials in adult patients with active RA. In all of the trials, patients treated with tocilizumab experienced greater improvement in their tender or swollen joints than patients given a placebo. The studies also showed that tocilizumab, alone or in combination with methotrexate or other DMARDs, significantly reduced RA signs and symptoms compared with DMARDs alone.

This First Report Managed Care Product Spotlight provides a summary of results from the RADIATE (Rheumatoid Arthritis Study in Anti-TNF Failures), OPTION (Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders), and TOWARD (Tocilizumab in Combination with Traditional DMARD Therapy) trials.

RADIATE TRIAL
Below is summary of a phase 3 trial that compared the safety and efficacy of tocilizumab with placebo for the treatment of patients with RA who failed TNF antagonist therapy.

Reference: Emery P, Keystone E, Tony HP, et al.
IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologics. Ann Rheum Dis. 2008;67:1516-1523.

Study Objective: The trial was designed to evaluate the effectiveness of tocilizumab with methotrexate in producing American College of Rheumatology 20% improvement (ACR20) response for RA patients refractory to treatment with ≥1 TNF antagonists.

Method
The trial was a randomized, placebo-controlled, double-blind, parallel-group study conducted in Western Europe and North America. Subjects were randomized to receive placebo or tocilizumab at a dosage of 8 or 4 mg/kg every 4 weeks for 24 weeks. Study medications were administered via a 1-hour IV infusion. Patients also received 10 to 25 mg of methotrexate weekly and folate. Other DMARDs were not allowed, but patients could continue to receive stable oral corticosteroids and/or other nonsteroidal anti-inflammatory drugs (NSAIDs).

Before receiving study medication patients had to discontinue other drug therapies, except for methotrexate, which they had to be receiving for ≥12 weeks before baseline. They could receive rescue therapy of 8 mg/kg tocilizumab plus methotrexate at week 16 in cases of treatment failure.

Population
The trial was open to patients age ≥18 with moderate-to-severe RA that had been active for ≥6 months and who failed to respond to treatment with ≥1 TNF antagonist therapy in the year preceding enrollment. Patients had swollen joint counts (SJCs) ≥6, tender joint counts (TJCs) ≥8, and C-reactive protein (CRP) >1.0 mg/dL or erythrocyte sedimentation rate (ESR) >28 mm/hour at baseline.

Patients were excluded if they had been treated with cell-depleting agents, had uncontrolled medical conditions or infections, a history of malignancies, or other inflammatory disease. All patients who received 1 or more administration of study treatment, the intention-to-treat (ITT) population, were included in the primary end point analysis.

The average age of study subjects was 54 in the tocilizumab 8-mg/kg group (n=170), 51 in the tocilizumab 4-mg/kg group (n=161), and 53 in the placebo group (n=158). About 80% were female, and the average disease duration was about 11.5 years. Investigators reported that the 3 treatment groups were reasonably well balanced for demographic and RA characteristics.

Primary end point:
•    Proportion of patients achieving ACR20 response at week 24

Secondary end points:
•    Proportion of patients achieving ACR50 and ACR70 response at week 24
•    Improvements in SJC and TJC

Results
At week 24, ACR20 response was achieved by 50.0% of patients in the tocilizumab 8-mg/kg group, and 30.4% of patients in the tocilizumab 4-mg/kg group, compared with 10.1% the control group (P<.001).

ACR50 response at week 24 was achieved by 28.8% of patients in the tocilizumab 8-mg/kg group and 16.8% of patients in the tocilizumab 4-mg/kg group, compared with 3.8% of patients in the control group (P<.001).

ACR70 response at week 24 was achieved by 12.4% (P=.001) of patients in the tocilizumab 8-mg/kg group and 5.0% (P=.01) of patients in the tocilizumab 4-mg/kg group, compared with 1.3% of patients in the control group.

SJCs were reduced by 7.8 in the tocilizumab 8-mg/kg group and 6.8 in the tocilizumab 4-mg/kg group, compared with a reduction of 0.5 in the control group (P<.001). TJCs were reduced by 14.8 in the tocilizumab 8-mg/kg group and 10.5 in the tocilizumab 4-mg/kg group, compared with a reduction of 0.3 in the control group (P<.001).

OPTION TRIAL
Below is summary of a phase 3 trial that compared the safety and efficacy of tocilizumab with placebo for the treatment of patients with RA who responded inadequately to methotrexate therapy.

Reference: Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION Study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008;371(9617):
987-997.

Study Objective: The trial was designed to evaluate the effectiveness of tocilizumab given with methotrexate at stable prestudy doses.

Method
The trial was a randomized, placebo-controlled, double-blind, parallel-group, international study. Subjects were randomized to receive placebo or tocilizumab at a dosage of 8 or 4 mg/kg at baseline and every 4 weeks for 24 weeks. They also received their stable weekly dose of methotrexate (10-25 mg), and all patients received a stable dose of folic acid (≥5 mg/week).

Patients discontinued treatment with all DMARDs before the start of the study. They could receive rescue therapy of 8 mg/kg tocilizumab and intra-articular steroids or increased oral corticosteroids if necessary.

Population
At 73 trial centers in 17 countries, the trial enrolled patients age ≥18 with moderate-to-severe RA that had been active for ≥6 months and who had an inadequate response to methotrexate therapy lasting at least 12 weeks before the study began. Patients had SJCs ≥6, TJCs ≥8, and CRP >1.0 mg/dL or ESR >28 mm/hour at baseline.

Patients were excluded if they had other autoimmune diseases or systemic involvement secondary to RA. The trial also excluded patients with functional class IV RA, other inflammatory diseases, or certain infections.

There were 622 patients in the ITT analysis for the primary end point. The average age of study subjects was about 51 years. There were 205 patients randomized to the tocilizumab 8-mg/kg group, 213 in the tocilizumab 4-mg/kg group, and 204 in the placebo group.

Primary end point:
•    Proportion of patients achieving ACR20 response at week 24

Secondary end points:
•    Proportion of patients achieving ACR50 and ACR70 response at week 24
•    Change from baseline disease activity score using 28 joint counts (DAS28) at 24 weeks

Results
At week 24, ACR20 response was achieved by 59% of patients in the tocilizumab 8-mg/kg group and 48% of patients in the tocilizumab 4-mg/kg group compared with 26% of patients who received placebo plus methotrexate (P<.0001).

ACR50 response at week 24 was achieved by 44% of patients in the tocilizumab 8-mg/kg group and 31% of patients in the tocilizumab 4-mg/kg group, compared with 11% of patients in the control group (P<.0001).

ACR70 response at week 24 was achieved by 22% of patients in the tocilizumab 8-mg/kg group and 12% of patients in the tocilizumab 4-mg/kg group, compared with 2% of patients in the control group (P<.0001).

DAS28 remission (DAS28 <2.6) at week 24 was achieved by 27% of patients in the tocilizumab 8-mg/kg group and 13% of patients in the tocilizumab 4-mg/kg group, compared with 0.8% of the placebo group.

TOWARD TRIAL
Below is summary of a phase 3 trial that compared the safety and efficacy of tocilizumab with placebo in RA patients receiving DMARD therapy.

Reference: Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2008;58(10):
2968-2980.

Study Objective: The trial was designed to evaluate the effectiveness of tocilizumab in combination with traditional DMARD therapy.

Method
The trial was a randomized, double-blind, placebo-controlled, international, multicenter study. While remaining on stable doses of DMARDs, subjects were randomized in a 2:1 ratio to receive 8 mg/kg of IV tocilizumab or placebo every 4 weeks. Folate at a stable dose of ≥5 mg/week was given to all patients. Methotrexate was the most commonly used DMARD.

Patients could continue to receive stable oral corticosteroids and NSAIDs/cyclooxygenase-2 inhibitors if the doses were stable for ≥6 weeks. Rescue therapy consisting of either adjusting the background DMARD and/or administration of another DMARD as well as intra-articular or oral glucocorticoids was available for patients who failed to achieve ≥20% improvement in SJC and TJC by week 16.

Population
In 18 countries, the trial enrolled patients age ≥18 years with moderate-to-severe RA that had been active for ≥6 months. Patients had SJCs ≥6, TJCs ≥8, and CRP >1.0 mg/dL or ESR >28 mm/hour at baseline.

The trial excluded patients treated unsuccessfully with anti-TNF therapy or who had received any cell-depleting therapy.

Of the 1220 patients randomized, there were 805 in the tocilizumab + DMARD group and 415 in the placebo + DMARD group. The ITT population included 803 and 413 patients, respectively, in the 2 groups. Average age was 53 years in the tocilizumab group and 54 years in the DMARD group. About 82% of subjects were female, and investigators reported that baseline disease characteristics, demographics, and concomitant medication use were well balanced between the groups.

Primary end point:
•    Proportion of patients achieving ACR20 response at week 24

Secondary end points:
•    Proportion of patients achieving ACR50 and ACR70 response at week 24
•    Time to onset of ACR20/50/70 responses

Results
At week 24, 61% of patients in the group that received tocilizumab 8 mg/kg plus DMARDs achieved ACR20 at 24 weeks, compared with 25% of patients treated with DMARDs + placebo. Investigators reported that there were more ACR20 responders who received tocilizumab in combination with any study DMARD than in patients who received DMARD + placebo, with no obvious differences in patients who received ≥2 DMARDs.

ACR50 response at week 24 was achieved by 38% of patients in the tocilizumab 8-mg/kg group compared with 9% of patients in the control group (P<.0001).

ACR70 response at week 24 was achieved by 21% of patients in the tocilizumab 8-mg/kg group compared with 3% of patients in the control group (P<.0001).

By the first scheduled assessment at week 2, there was a separation observed in both ACR20 and ACR50 responses between the treatment groups. By week 4, there was a separation between the groups in ACR70 response.

Safety Notes
The US Food and Drug Administration (FDA) is requiring the sponsor to conduct a postmarketing clinical trial to further evaluate the long-term safety of Actemra. Specifically, the FDA wants to evaluate the impact of elevated LDL-C and blood pressure seen in some patients in shorter-term trials on the cardiovascular health of patients treated with Actemra.

In addition, a Risk Evaluation and Mitigation Strategy (REMS) will require the drug sponsor to implement a Communication Plan for physicians, informing them how to appropriately monitor their patients for liver and/or gastrointestinal side effects. The REMS will include a Medication Guide to ensure that patients are informed of the benefits and risks of Actemra.

The most common adverse reactions in clinical trials were upper respiratory tract infections, headache, inflammation of the nose or nasal passage, high blood pressure, and increased liver enzymes. Elevations in LDL-C were also seen in some patients, some of whom required the addition of lipid-lowering agents.

Patients treated with Actemra are at increased risk for developing serious infections. Most patients who developed these infections in clinical trials were also taking other drugs that suppress the immune system, such as methotrexate or corticosteroids.

Actemra Facts
•    Actemra is marketed by Genentech Inc, a subsidiary of the Roche Group
•    Actemra was approved on January 11, 2010
•    Actemra is the first medication designed to specifically inhibit IL-6
•    The clinical trial program for Actemra enrolled >4000 people with RA
•    In the European Union, tocilizumab is marketed as RoActemra

Additional Resources

Prescribing Information for Actemra: www.gene.com/gene/products/information/actemra/pdf/pi.pdf

Medication Guide for Actemra: www.actemra.com