Long-Acting IL Inhibitor Promising in Systemic JIA

BOSTON — Data emerging from the open-label extension period of a phase II trial of rilonacept for systemic juvenile idiopathic arthritis are showing “obvious clinical benefits,” despite disappointing results from the double-blind portion of the study, Dr. Daniel J. Lovell said at the annual meeting of the American College of Rheumatology.

Rilonacept is a long-acting inhibitor of both the interleukin (IL)-1α gene and IL-2β gene that has been shown to be “strikingly effective” in clinical studies of diseases known to be driven by IL-1 overexpression, such as familial cold autoinflammatory syndrome and Muckle Wells syndrome, Dr. Lovell said.

Uncontrolled studies have demonstrated clinical benefits with a short-acting IL-1 inhibitor in systemic juvenile idiopathic arthritis (JIA), suggesting that this cytokine plays a pivotal role in the disease.

The study, which was supported by Regeneron Pharmaceuticals Inc., is ongoing, and a phase III study is planned and will be funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, he said.

Dr. Lovell disclosed that he has received consulting fees from Regeneron.

The study included 24 patients aged 5–20 years who have active systemic JIA. Most were white females who had had either a fever or rash during the previous 2 weeks that was accompanied by functional limitations. They also had abnormal laboratory markers including elevated C-reactive protein, white blood cell counts, and platelets; and lower than normal hemoglobin levels.

At baseline, disease was assessed as very active on both physician and parent global assessment, the mean number of active joints was 16, and the mean childhood health assessment questionnaire score was 1.4. Patients were permitted to enroll if they had previously failed prior biologic therapies including the IL-1 receptor antagonist anakinra, said Dr. Lovell, a pediatric rheumatologist at Cincinnati Children's Hospital Medical Center, and professor of pediatrics, University of Cincinnati.

During the 4-week double-blind phase of the trial, patients received placebo or 2.2 mg/kg or 4.4 mg/kg of rilonacept subcutaneously once weekly. The number of patients in each of these groups was seven, eight, and nine, respectively.

Response was assessed according to the ACR Pediatric 30 criteria, which require a 30% improvement in at least three of the core disease components and a worsening of no more than 30% in one component. The core disease components in JIA include physician and parent global assessments, number of joints with active arthritis, number of joints with limited motion, childhood health assessment questionnaire score, and laboratory values such as C-reactive protein. An adapted version of the ACR Pediatric 30 response, targeted for use in systemic JIA, also includes the presence of fever or rash.

By the end of the double-blind phase, an ACR Pediatric 30 response had been reached by two (29%) patients in the placebo group, four (50%) of those in the 2.2-mg/kg group, two (22%) in the 4.4-mg/kg group, and a total of six (35%) in the two active-treatment groups combined.

These differences were not statistically significant. “So if this was the end of the story, we would go home and say rilonacept was not effective in this patient population. But that would be premature because of the small sample size—and also because the story is more complex than that. These patients went on to be treated with rilonacept for at least 52 weeks, and the data from the open-label extension are important for us to look at,” Dr. Lovell said.

Ten of the 24 patients withdrew from the study for lack of efficacy, poor tolerance, or other unrelated reasons, and 3 continued with treatment but did not reach an ACR Pediatric 30 response. Among the remaining 11 patients, 10 demonstrated an ACR Pediatric 70 or greater response by week 52, and 1 additional patient reached an ACR Pediatric 30 response. Fever and rash had resolved in all patients, and laboratory parameters had improved substantially. “So in up to 48% of patients, there was an obvious clinical benefit that persisted through 52 weeks,” he said.

Only four serious adverse events were seen in the trial, none of which was thought by the investigators to be related to the treatment.

Among the lessons learned from this study was that 4 weeks was not long enough to demonstrate full response to the drug in systemic JIA, according to Dr. Lovell.

BOSTON — Data emerging from the open-label extension period of a phase II trial of rilonacept for systemic juvenile idiopathic arthritis are showing “obvious clinical benefits,” despite disappointing results from the double-blind portion of the study, Dr. Daniel J. Lovell said at the annual meeting of the American College of Rheumatology.

Rilonacept is a long-acting inhibitor of both the interleukin (IL)-1α gene and IL-2β gene that has been shown to be “strikingly effective” in clinical studies of diseases known to be driven by IL-1 overexpression, such as familial cold autoinflammatory syndrome and Muckle Wells syndrome, Dr. Lovell said.

Uncontrolled studies have demonstrated clinical benefits with a short-acting IL-1 inhibitor in systemic juvenile idiopathic arthritis (JIA), suggesting that this cytokine plays a pivotal role in the disease.

The study, which was supported by Regeneron Pharmaceuticals Inc., is ongoing, and a phase III study is planned and will be funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, he said.

Dr. Lovell disclosed that he has received consulting fees from Regeneron.

The study included 24 patients aged 5–20 years who have active systemic JIA. Most were white females who had had either a fever or rash during the previous 2 weeks that was accompanied by functional limitations. They also had abnormal laboratory markers including elevated C-reactive protein, white blood cell counts, and platelets; and lower than normal hemoglobin levels.

At baseline, disease was assessed as very active on both physician and parent global assessment, the mean number of active joints was 16, and the mean childhood health assessment questionnaire score was 1.4. Patients were permitted to enroll if they had previously failed prior biologic therapies including the IL-1 receptor antagonist anakinra, said Dr. Lovell, a pediatric rheumatologist at Cincinnati Children's Hospital Medical Center, and professor of pediatrics, University of Cincinnati.

During the 4-week double-blind phase of the trial, patients received placebo or 2.2 mg/kg or 4.4 mg/kg of rilonacept subcutaneously once weekly. The number of patients in each of these groups was seven, eight, and nine, respectively.

Response was assessed according to the ACR Pediatric 30 criteria, which require a 30% improvement in at least three of the core disease components and a worsening of no more than 30% in one component. The core disease components in JIA include physician and parent global assessments, number of joints with active arthritis, number of joints with limited motion, childhood health assessment questionnaire score, and laboratory values such as C-reactive protein. An adapted version of the ACR Pediatric 30 response, targeted for use in systemic JIA, also includes the presence of fever or rash.

By the end of the double-blind phase, an ACR Pediatric 30 response had been reached by two (29%) patients in the placebo group, four (50%) of those in the 2.2-mg/kg group, two (22%) in the 4.4-mg/kg group, and a total of six (35%) in the two active-treatment groups combined.

These differences were not statistically significant. “So if this was the end of the story, we would go home and say rilonacept was not effective in this patient population. But that would be premature because of the small sample size—and also because the story is more complex than that. These patients went on to be treated with rilonacept for at least 52 weeks, and the data from the open-label extension are important for us to look at,” Dr. Lovell said.

Ten of the 24 patients withdrew from the study for lack of efficacy, poor tolerance, or other unrelated reasons, and 3 continued with treatment but did not reach an ACR Pediatric 30 response. Among the remaining 11 patients, 10 demonstrated an ACR Pediatric 70 or greater response by week 52, and 1 additional patient reached an ACR Pediatric 30 response. Fever and rash had resolved in all patients, and laboratory parameters had improved substantially. “So in up to 48% of patients, there was an obvious clinical benefit that persisted through 52 weeks,” he said.

Only four serious adverse events were seen in the trial, none of which was thought by the investigators to be related to the treatment.

Among the lessons learned from this study was that 4 weeks was not long enough to demonstrate full response to the drug in systemic JIA, according to Dr. Lovell.

BOSTON — Data emerging from the open-label extension period of a phase II trial of rilonacept for systemic juvenile idiopathic arthritis are showing “obvious clinical benefits,” despite disappointing results from the double-blind portion of the study, Dr. Daniel J. Lovell said at the annual meeting of the American College of Rheumatology.

Rilonacept is a long-acting inhibitor of both the interleukin (IL)-1α gene and IL-2β gene that has been shown to be “strikingly effective” in clinical studies of diseases known to be driven by IL-1 overexpression, such as familial cold autoinflammatory syndrome and Muckle Wells syndrome, Dr. Lovell said.

Uncontrolled studies have demonstrated clinical benefits with a short-acting IL-1 inhibitor in systemic juvenile idiopathic arthritis (JIA), suggesting that this cytokine plays a pivotal role in the disease.

The study, which was supported by Regeneron Pharmaceuticals Inc., is ongoing, and a phase III study is planned and will be funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, he said.

Dr. Lovell disclosed that he has received consulting fees from Regeneron.

The study included 24 patients aged 5–20 years who have active systemic JIA. Most were white females who had had either a fever or rash during the previous 2 weeks that was accompanied by functional limitations. They also had abnormal laboratory markers including elevated C-reactive protein, white blood cell counts, and platelets; and lower than normal hemoglobin levels.

At baseline, disease was assessed as very active on both physician and parent global assessment, the mean number of active joints was 16, and the mean childhood health assessment questionnaire score was 1.4. Patients were permitted to enroll if they had previously failed prior biologic therapies including the IL-1 receptor antagonist anakinra, said Dr. Lovell, a pediatric rheumatologist at Cincinnati Children's Hospital Medical Center, and professor of pediatrics, University of Cincinnati.

During the 4-week double-blind phase of the trial, patients received placebo or 2.2 mg/kg or 4.4 mg/kg of rilonacept subcutaneously once weekly. The number of patients in each of these groups was seven, eight, and nine, respectively.

Response was assessed according to the ACR Pediatric 30 criteria, which require a 30% improvement in at least three of the core disease components and a worsening of no more than 30% in one component. The core disease components in JIA include physician and parent global assessments, number of joints with active arthritis, number of joints with limited motion, childhood health assessment questionnaire score, and laboratory values such as C-reactive protein. An adapted version of the ACR Pediatric 30 response, targeted for use in systemic JIA, also includes the presence of fever or rash.

By the end of the double-blind phase, an ACR Pediatric 30 response had been reached by two (29%) patients in the placebo group, four (50%) of those in the 2.2-mg/kg group, two (22%) in the 4.4-mg/kg group, and a total of six (35%) in the two active-treatment groups combined.

These differences were not statistically significant. “So if this was the end of the story, we would go home and say rilonacept was not effective in this patient population. But that would be premature because of the small sample size—and also because the story is more complex than that. These patients went on to be treated with rilonacept for at least 52 weeks, and the data from the open-label extension are important for us to look at,” Dr. Lovell said.

Ten of the 24 patients withdrew from the study for lack of efficacy, poor tolerance, or other unrelated reasons, and 3 continued with treatment but did not reach an ACR Pediatric 30 response. Among the remaining 11 patients, 10 demonstrated an ACR Pediatric 70 or greater response by week 52, and 1 additional patient reached an ACR Pediatric 30 response. Fever and rash had resolved in all patients, and laboratory parameters had improved substantially. “So in up to 48% of patients, there was an obvious clinical benefit that persisted through 52 weeks,” he said.

Only four serious adverse events were seen in the trial, none of which was thought by the investigators to be related to the treatment.

Among the lessons learned from this study was that 4 weeks was not long enough to demonstrate full response to the drug in systemic JIA, according to Dr. Lovell.