Sirukumab improves rheumatoid arthritis symptoms in phase II trial

The investigational drug sirukumab significantly improved signs and symptoms of rheumatoid arthritis in a phase II trial of patients who had active disease despite receiving methotrexate.

The multicenter, randomized, placebo-controlled, double-blind study found that the drug, a human anti–interleukin (IL)-6 monoclonal antibody, led to significant improvements in American College of Rheumatology (ACR) criteria 50 and 20 responses, 28-joint count Disease Activity Score using C-reactive protein (DAS28-CRP), and scores on the Health Assessment Questionnaire-disability index (HAQ-DI) and Clinical Disease Activity Index (CDAI), compared with placebo. Of five sirukumab treatment arms in the trial, the most effective dose was 100 mg every 2 weeks.

Differences in ACR20 and ACR50 response rates between the sirukumab groups versus placebo at week 12 in the study "were generally broadly consistent with those achieved with the anti-IL-6 receptor antibodies tocilizumab and sarilumab, and the anti-IL-6 antibody clazakizumab in patients with an inadequate response to prior [methotrexate] therapy," wrote lead investigator Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, Vienna, and his colleagues.

In the two-part study, the investigators recruited adults from sites across Europe, North America, and Asia who had active RA despite methotrexate therapy. For the first part, 36 patients were randomized to receive either an injection of 100 mg of sirukumab or placebo every 2 weeks for 10 weeks and then switch to the other regimen for the next 12 weeks. For the second part, 151 patients were randomly assigned to one of five groups: injections of sirukumab at a dose of 100 mg every 2 weeks, 100 mg every 4 weeks, 50 mg every 4 weeks, 25 mg every 4 weeks for 24 weeks, and placebo every 2 weeks for 12 weeks (followed by 100 mg sirukumab every 2 weeks for 12 weeks).

In part 1, patients who received sirukumab at 100 mg every 2 weeks had a "significantly greater mean improvement from baseline to week 12 in DAS28-CRP (2.1 vs. 0.6)" than did those receiving placebo, the investigators said. Patients receiving sirukumab also had significantly greater ACR20 response rates (71% vs. 18%) and greater improvements in HAQ-DI (0.74 vs. 0.17) and CDAI (16.7 vs. 7.2) scores. At 12 weeks, 29% of patients treated with sirukumab achieved ACR50 responses, compared with 6% of patients who received placebo. Clinical responses to the 100-mg dose of sirukumab occurred as early as the second week of the study.

Patients who originally received placebo and were switched to sirukumab quickly achieved a clinical response similar to the patients who originally received the drug. Among patients switched from active drug to placebo, the clinical response lasted through the study’s end.

In part 2 of the study, only the group receiving 100 mg of sirukumab every 2 weeks achieved a statistically significant difference from placebo in ACR50 response rates at 12 weeks (the primary endpoint), occurring in 27% of the drug group versus 3% of the placebo group. ACR20 responses also were significantly higher in the 100-mg sirukumab groups versus placebo.

The authors noted that all four sirukumab groups had "a significantly greater mean improvement in DAS28-CRP at week 12 versus placebo." Six patients receiving 100 mg sirukumab every 2 weeks achieved DAS28-CRP remission versus none on placebo; patients receiving that sirukumab dose also had a greater improvement in CDAI scores (20.7 vs. 13.3).

"This study demonstrates proof-of-concept that IL-6 blockade by sirukumab provides a biologic therapy for RA," the authors wrote (Ann. Rheum. Dis. 2014 April 3 [doi:10.1136/annrheumdis-2013-205137).

Researchers observed decreases in white blood cells, neutrophils, and platelets in all sirukumab groups, generally within 2 weeks of starting treatment.

In part 1, 24 patients before crossover reported at least one adverse effect and 25 reported at least one after crossover. In part 2, 119 patients reported at least one adverse effect. Adverse effects were most often infections such as nasopharyngitis and upper respiratory tract infections. Serious adverse effects, including pneumonia, were reported by 1 patient in part 1 and 17 patients in part 2.

Phase III trials of the drug are ongoing.

This study was supported by Janssen Research & Development (a division of Johnson & Johnson). Three of the five study authors are employees of the study sponsor and own stock in Johnson & Johnson. Dr. Smolen and a coauthor have received grants and/or fees from multiple pharmaceutical companies, including Janssen.

The investigational drug sirukumab significantly improved signs and symptoms of rheumatoid arthritis in a phase II trial of patients who had active disease despite receiving methotrexate.

The multicenter, randomized, placebo-controlled, double-blind study found that the drug, a human anti–interleukin (IL)-6 monoclonal antibody, led to significant improvements in American College of Rheumatology (ACR) criteria 50 and 20 responses, 28-joint count Disease Activity Score using C-reactive protein (DAS28-CRP), and scores on the Health Assessment Questionnaire-disability index (HAQ-DI) and Clinical Disease Activity Index (CDAI), compared with placebo. Of five sirukumab treatment arms in the trial, the most effective dose was 100 mg every 2 weeks.

Differences in ACR20 and ACR50 response rates between the sirukumab groups versus placebo at week 12 in the study "were generally broadly consistent with those achieved with the anti-IL-6 receptor antibodies tocilizumab and sarilumab, and the anti-IL-6 antibody clazakizumab in patients with an inadequate response to prior [methotrexate] therapy," wrote lead investigator Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, Vienna, and his colleagues.

In the two-part study, the investigators recruited adults from sites across Europe, North America, and Asia who had active RA despite methotrexate therapy. For the first part, 36 patients were randomized to receive either an injection of 100 mg of sirukumab or placebo every 2 weeks for 10 weeks and then switch to the other regimen for the next 12 weeks. For the second part, 151 patients were randomly assigned to one of five groups: injections of sirukumab at a dose of 100 mg every 2 weeks, 100 mg every 4 weeks, 50 mg every 4 weeks, 25 mg every 4 weeks for 24 weeks, and placebo every 2 weeks for 12 weeks (followed by 100 mg sirukumab every 2 weeks for 12 weeks).

In part 1, patients who received sirukumab at 100 mg every 2 weeks had a "significantly greater mean improvement from baseline to week 12 in DAS28-CRP (2.1 vs. 0.6)" than did those receiving placebo, the investigators said. Patients receiving sirukumab also had significantly greater ACR20 response rates (71% vs. 18%) and greater improvements in HAQ-DI (0.74 vs. 0.17) and CDAI (16.7 vs. 7.2) scores. At 12 weeks, 29% of patients treated with sirukumab achieved ACR50 responses, compared with 6% of patients who received placebo. Clinical responses to the 100-mg dose of sirukumab occurred as early as the second week of the study.

Patients who originally received placebo and were switched to sirukumab quickly achieved a clinical response similar to the patients who originally received the drug. Among patients switched from active drug to placebo, the clinical response lasted through the study’s end.

In part 2 of the study, only the group receiving 100 mg of sirukumab every 2 weeks achieved a statistically significant difference from placebo in ACR50 response rates at 12 weeks (the primary endpoint), occurring in 27% of the drug group versus 3% of the placebo group. ACR20 responses also were significantly higher in the 100-mg sirukumab groups versus placebo.

The authors noted that all four sirukumab groups had "a significantly greater mean improvement in DAS28-CRP at week 12 versus placebo." Six patients receiving 100 mg sirukumab every 2 weeks achieved DAS28-CRP remission versus none on placebo; patients receiving that sirukumab dose also had a greater improvement in CDAI scores (20.7 vs. 13.3).

"This study demonstrates proof-of-concept that IL-6 blockade by sirukumab provides a biologic therapy for RA," the authors wrote (Ann. Rheum. Dis. 2014 April 3 [doi:10.1136/annrheumdis-2013-205137).

Researchers observed decreases in white blood cells, neutrophils, and platelets in all sirukumab groups, generally within 2 weeks of starting treatment.

In part 1, 24 patients before crossover reported at least one adverse effect and 25 reported at least one after crossover. In part 2, 119 patients reported at least one adverse effect. Adverse effects were most often infections such as nasopharyngitis and upper respiratory tract infections. Serious adverse effects, including pneumonia, were reported by 1 patient in part 1 and 17 patients in part 2.

Phase III trials of the drug are ongoing.

This study was supported by Janssen Research & Development (a division of Johnson & Johnson). Three of the five study authors are employees of the study sponsor and own stock in Johnson & Johnson. Dr. Smolen and a coauthor have received grants and/or fees from multiple pharmaceutical companies, including Janssen.

The investigational drug sirukumab significantly improved signs and symptoms of rheumatoid arthritis in a phase II trial of patients who had active disease despite receiving methotrexate.

The multicenter, randomized, placebo-controlled, double-blind study found that the drug, a human anti–interleukin (IL)-6 monoclonal antibody, led to significant improvements in American College of Rheumatology (ACR) criteria 50 and 20 responses, 28-joint count Disease Activity Score using C-reactive protein (DAS28-CRP), and scores on the Health Assessment Questionnaire-disability index (HAQ-DI) and Clinical Disease Activity Index (CDAI), compared with placebo. Of five sirukumab treatment arms in the trial, the most effective dose was 100 mg every 2 weeks.

Differences in ACR20 and ACR50 response rates between the sirukumab groups versus placebo at week 12 in the study "were generally broadly consistent with those achieved with the anti-IL-6 receptor antibodies tocilizumab and sarilumab, and the anti-IL-6 antibody clazakizumab in patients with an inadequate response to prior [methotrexate] therapy," wrote lead investigator Dr. Josef S. Smolen of the Medical University of Vienna and Hietzing Hospital, Vienna, and his colleagues.

In the two-part study, the investigators recruited adults from sites across Europe, North America, and Asia who had active RA despite methotrexate therapy. For the first part, 36 patients were randomized to receive either an injection of 100 mg of sirukumab or placebo every 2 weeks for 10 weeks and then switch to the other regimen for the next 12 weeks. For the second part, 151 patients were randomly assigned to one of five groups: injections of sirukumab at a dose of 100 mg every 2 weeks, 100 mg every 4 weeks, 50 mg every 4 weeks, 25 mg every 4 weeks for 24 weeks, and placebo every 2 weeks for 12 weeks (followed by 100 mg sirukumab every 2 weeks for 12 weeks).

In part 1, patients who received sirukumab at 100 mg every 2 weeks had a "significantly greater mean improvement from baseline to week 12 in DAS28-CRP (2.1 vs. 0.6)" than did those receiving placebo, the investigators said. Patients receiving sirukumab also had significantly greater ACR20 response rates (71% vs. 18%) and greater improvements in HAQ-DI (0.74 vs. 0.17) and CDAI (16.7 vs. 7.2) scores. At 12 weeks, 29% of patients treated with sirukumab achieved ACR50 responses, compared with 6% of patients who received placebo. Clinical responses to the 100-mg dose of sirukumab occurred as early as the second week of the study.

Patients who originally received placebo and were switched to sirukumab quickly achieved a clinical response similar to the patients who originally received the drug. Among patients switched from active drug to placebo, the clinical response lasted through the study’s end.

In part 2 of the study, only the group receiving 100 mg of sirukumab every 2 weeks achieved a statistically significant difference from placebo in ACR50 response rates at 12 weeks (the primary endpoint), occurring in 27% of the drug group versus 3% of the placebo group. ACR20 responses also were significantly higher in the 100-mg sirukumab groups versus placebo.

The authors noted that all four sirukumab groups had "a significantly greater mean improvement in DAS28-CRP at week 12 versus placebo." Six patients receiving 100 mg sirukumab every 2 weeks achieved DAS28-CRP remission versus none on placebo; patients receiving that sirukumab dose also had a greater improvement in CDAI scores (20.7 vs. 13.3).

"This study demonstrates proof-of-concept that IL-6 blockade by sirukumab provides a biologic therapy for RA," the authors wrote (Ann. Rheum. Dis. 2014 April 3 [doi:10.1136/annrheumdis-2013-205137).

Researchers observed decreases in white blood cells, neutrophils, and platelets in all sirukumab groups, generally within 2 weeks of starting treatment.

In part 1, 24 patients before crossover reported at least one adverse effect and 25 reported at least one after crossover. In part 2, 119 patients reported at least one adverse effect. Adverse effects were most often infections such as nasopharyngitis and upper respiratory tract infections. Serious adverse effects, including pneumonia, were reported by 1 patient in part 1 and 17 patients in part 2.

Phase III trials of the drug are ongoing.

This study was supported by Janssen Research & Development (a division of Johnson & Johnson). Three of the five study authors are employees of the study sponsor and own stock in Johnson & Johnson. Dr. Smolen and a coauthor have received grants and/or fees from multiple pharmaceutical companies, including Janssen.