Canakinumab shown effective against systemic JIA

Canakinumab, a monoclonal antibody that selectively inactivates interleukin-1 signaling, was effective in controlling symptoms and preventing flare-ups of systemic juvenile idiopathic arthritis in two phase III clinical trials reported online Dec. 20 in the New England Journal of Medicine.

The agent inactivated JIA in one-third of the patients in the first trial within 2 weeks, and it maintained inactive status for 2 years in 62% of the patients in the second trial. "These findings confirm, in a controlled setting, previous observations with anakinra [another anti-interleukin-1 agent], which suggested that about 40% of patients with systemic JIA have a dramatic and persistent response to anti-interleukin-1 therapy," said Dr. Nicolino Ruperto of the Istituto Giannina Gaslini, Genoa, Italy, and his associates.

"This is similar to response rates observed in some autoinflammatory diseases and in trials with anti-interleukin-6 medications," they noted.

Dr. Ruperto and his colleagues evaluated the efficacy and safety of canakinumab in the two trials, drawing study subjects from 63 medical centers that were members of PRINTO (the Paediatric Rheumatology International Trials Organisation) and PRCSG (the Pediatric Rheumatology Collaborative Study). Both trials were funded by Novartis Pharma, which also designed and managed the current study and the data analysis.

Trial 1 was a 1-month single-dose study in which 84 patients aged 2-19 years who had active systemic JIA were randomly assigned to receive either subcutaneous canakinumab (43 subjects) or a matching placebo (41 subjects) in a double-blind fashion. At 15 days, the primary outcome was assessed: an adapted JIA American College of Rheumatology 30 (JIA ACR 30) response, defined as improvement of 30% or more in three or more of the six variables in the JIA core set, with no more than one variable worsening by more than 30%, plus an absence of fever.

Thirty-six patients (84%) of the canakinumab group achieved this endpoint, compared with only four patients (10%) in the placebo group. The responders were automatically enrolled in the second, longer-term clinical trial. In addition, subjects in the placebo group who had persistent fever after day 3 were allowed to immediately enroll in trial 2 at the discretion of their treating physicians.

In trial 2, the first phase involved 177 patients who received open-label canakinumab injections every 4 weeks for 12-32 weeks. The second phase involved randomly assigning treatment responders, who had either discontinued or tapered their glucocorticoid dose, to either continued treatment (50 patients) or placebo injections (50 patients) in a double-blind fashion. In this withdrawal phase, patients who had a disease flare were switched to open-label canakinumab.

In addition, all patients who were unable to taper glucocorticoids or who had not responded to the open-label phase were permitted to enter the open-label extension of trial 2. Clinical assessments were performed monthly.

At the end of the open-label phase of trial 2, when subjects had participated for a median of 113 days and had received a median of 4 injections of canakinumab, 73% achieved an adapted JIA ACR 50 response, including 31% who had inactive disease.

During the withdrawal phase, the median time to a disease flare was 236 days for the placebo group but was "not observable" in the canakinumab group because less than half of the patients experienced a disease flare.

During extended follow-up, 74% of the canakinumab group had no disease flares, compared with only 25% of the placebo group. This represents a significant relative risk reduction of 64% regarding disease flares.

Approximately one-third of the study subjects were able to discontinue glucocorticoids completely within 7 months of beginning canakinumab, and approximately half were able to taper their dose markedly. This greatly decreased the burden of glucocorticoid toxicity, the investigators said (N. Engl. J. Med. 2012;367:2396-406).

The most common adverse effects were infections, which occurred at a similar rate between patients receiving active treatment and those receiving placebo. Neutropenia and thrombocytopenia were mostly transient and were not associated with an increase in infection or bleeding complications, the researchers said.

One patient, a 13-year-old boy who had previously been treated with anakinra and tocilizumab, was hospitalized for adenovirus gastroenteritis, which resolved. Four days later, after he received his third dose of canakinumab, he required rehospitalization for macrophage activation syndrome. He developed severe pulmonary hypertension and died 3 weeks later.

These trials were limited in their ability to assess safety, given the short duration of exposure to placebo in both trials and the use of a withdrawal design. Longer-term safety data are needed, Dr. Ruperto and his associates said.

Canakinumab, a monoclonal antibody that selectively inactivates interleukin-1 signaling, was effective in controlling symptoms and preventing flare-ups of systemic juvenile idiopathic arthritis in two phase III clinical trials reported online Dec. 20 in the New England Journal of Medicine.

The agent inactivated JIA in one-third of the patients in the first trial within 2 weeks, and it maintained inactive status for 2 years in 62% of the patients in the second trial. "These findings confirm, in a controlled setting, previous observations with anakinra [another anti-interleukin-1 agent], which suggested that about 40% of patients with systemic JIA have a dramatic and persistent response to anti-interleukin-1 therapy," said Dr. Nicolino Ruperto of the Istituto Giannina Gaslini, Genoa, Italy, and his associates.

"This is similar to response rates observed in some autoinflammatory diseases and in trials with anti-interleukin-6 medications," they noted.

Dr. Ruperto and his colleagues evaluated the efficacy and safety of canakinumab in the two trials, drawing study subjects from 63 medical centers that were members of PRINTO (the Paediatric Rheumatology International Trials Organisation) and PRCSG (the Pediatric Rheumatology Collaborative Study). Both trials were funded by Novartis Pharma, which also designed and managed the current study and the data analysis.

Trial 1 was a 1-month single-dose study in which 84 patients aged 2-19 years who had active systemic JIA were randomly assigned to receive either subcutaneous canakinumab (43 subjects) or a matching placebo (41 subjects) in a double-blind fashion. At 15 days, the primary outcome was assessed: an adapted JIA American College of Rheumatology 30 (JIA ACR 30) response, defined as improvement of 30% or more in three or more of the six variables in the JIA core set, with no more than one variable worsening by more than 30%, plus an absence of fever.

Thirty-six patients (84%) of the canakinumab group achieved this endpoint, compared with only four patients (10%) in the placebo group. The responders were automatically enrolled in the second, longer-term clinical trial. In addition, subjects in the placebo group who had persistent fever after day 3 were allowed to immediately enroll in trial 2 at the discretion of their treating physicians.

In trial 2, the first phase involved 177 patients who received open-label canakinumab injections every 4 weeks for 12-32 weeks. The second phase involved randomly assigning treatment responders, who had either discontinued or tapered their glucocorticoid dose, to either continued treatment (50 patients) or placebo injections (50 patients) in a double-blind fashion. In this withdrawal phase, patients who had a disease flare were switched to open-label canakinumab.

In addition, all patients who were unable to taper glucocorticoids or who had not responded to the open-label phase were permitted to enter the open-label extension of trial 2. Clinical assessments were performed monthly.

At the end of the open-label phase of trial 2, when subjects had participated for a median of 113 days and had received a median of 4 injections of canakinumab, 73% achieved an adapted JIA ACR 50 response, including 31% who had inactive disease.

During the withdrawal phase, the median time to a disease flare was 236 days for the placebo group but was "not observable" in the canakinumab group because less than half of the patients experienced a disease flare.

During extended follow-up, 74% of the canakinumab group had no disease flares, compared with only 25% of the placebo group. This represents a significant relative risk reduction of 64% regarding disease flares.

Approximately one-third of the study subjects were able to discontinue glucocorticoids completely within 7 months of beginning canakinumab, and approximately half were able to taper their dose markedly. This greatly decreased the burden of glucocorticoid toxicity, the investigators said (N. Engl. J. Med. 2012;367:2396-406).

The most common adverse effects were infections, which occurred at a similar rate between patients receiving active treatment and those receiving placebo. Neutropenia and thrombocytopenia were mostly transient and were not associated with an increase in infection or bleeding complications, the researchers said.

One patient, a 13-year-old boy who had previously been treated with anakinra and tocilizumab, was hospitalized for adenovirus gastroenteritis, which resolved. Four days later, after he received his third dose of canakinumab, he required rehospitalization for macrophage activation syndrome. He developed severe pulmonary hypertension and died 3 weeks later.

These trials were limited in their ability to assess safety, given the short duration of exposure to placebo in both trials and the use of a withdrawal design. Longer-term safety data are needed, Dr. Ruperto and his associates said.

Canakinumab, a monoclonal antibody that selectively inactivates interleukin-1 signaling, was effective in controlling symptoms and preventing flare-ups of systemic juvenile idiopathic arthritis in two phase III clinical trials reported online Dec. 20 in the New England Journal of Medicine.

The agent inactivated JIA in one-third of the patients in the first trial within 2 weeks, and it maintained inactive status for 2 years in 62% of the patients in the second trial. "These findings confirm, in a controlled setting, previous observations with anakinra [another anti-interleukin-1 agent], which suggested that about 40% of patients with systemic JIA have a dramatic and persistent response to anti-interleukin-1 therapy," said Dr. Nicolino Ruperto of the Istituto Giannina Gaslini, Genoa, Italy, and his associates.

"This is similar to response rates observed in some autoinflammatory diseases and in trials with anti-interleukin-6 medications," they noted.

Dr. Ruperto and his colleagues evaluated the efficacy and safety of canakinumab in the two trials, drawing study subjects from 63 medical centers that were members of PRINTO (the Paediatric Rheumatology International Trials Organisation) and PRCSG (the Pediatric Rheumatology Collaborative Study). Both trials were funded by Novartis Pharma, which also designed and managed the current study and the data analysis.

Trial 1 was a 1-month single-dose study in which 84 patients aged 2-19 years who had active systemic JIA were randomly assigned to receive either subcutaneous canakinumab (43 subjects) or a matching placebo (41 subjects) in a double-blind fashion. At 15 days, the primary outcome was assessed: an adapted JIA American College of Rheumatology 30 (JIA ACR 30) response, defined as improvement of 30% or more in three or more of the six variables in the JIA core set, with no more than one variable worsening by more than 30%, plus an absence of fever.

Thirty-six patients (84%) of the canakinumab group achieved this endpoint, compared with only four patients (10%) in the placebo group. The responders were automatically enrolled in the second, longer-term clinical trial. In addition, subjects in the placebo group who had persistent fever after day 3 were allowed to immediately enroll in trial 2 at the discretion of their treating physicians.

In trial 2, the first phase involved 177 patients who received open-label canakinumab injections every 4 weeks for 12-32 weeks. The second phase involved randomly assigning treatment responders, who had either discontinued or tapered their glucocorticoid dose, to either continued treatment (50 patients) or placebo injections (50 patients) in a double-blind fashion. In this withdrawal phase, patients who had a disease flare were switched to open-label canakinumab.

In addition, all patients who were unable to taper glucocorticoids or who had not responded to the open-label phase were permitted to enter the open-label extension of trial 2. Clinical assessments were performed monthly.

At the end of the open-label phase of trial 2, when subjects had participated for a median of 113 days and had received a median of 4 injections of canakinumab, 73% achieved an adapted JIA ACR 50 response, including 31% who had inactive disease.

During the withdrawal phase, the median time to a disease flare was 236 days for the placebo group but was "not observable" in the canakinumab group because less than half of the patients experienced a disease flare.

During extended follow-up, 74% of the canakinumab group had no disease flares, compared with only 25% of the placebo group. This represents a significant relative risk reduction of 64% regarding disease flares.

Approximately one-third of the study subjects were able to discontinue glucocorticoids completely within 7 months of beginning canakinumab, and approximately half were able to taper their dose markedly. This greatly decreased the burden of glucocorticoid toxicity, the investigators said (N. Engl. J. Med. 2012;367:2396-406).

The most common adverse effects were infections, which occurred at a similar rate between patients receiving active treatment and those receiving placebo. Neutropenia and thrombocytopenia were mostly transient and were not associated with an increase in infection or bleeding complications, the researchers said.

One patient, a 13-year-old boy who had previously been treated with anakinra and tocilizumab, was hospitalized for adenovirus gastroenteritis, which resolved. Four days later, after he received his third dose of canakinumab, he required rehospitalization for macrophage activation syndrome. He developed severe pulmonary hypertension and died 3 weeks later.

These trials were limited in their ability to assess safety, given the short duration of exposure to placebo in both trials and the use of a withdrawal design. Longer-term safety data are needed, Dr. Ruperto and his associates said.