Tocilizumab may be effective in treating JIA

[Mike Bartolatz]

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NEW THERAPY, TOCILIZUMAB, MAY BE EFFECTIVE AT TREATING CHILDREN WITH JUVENILE ARTHRITIS
WASHINGTON, DC – Researchers found that tocilizumab, an anti-IL6 receptor monoclonal antibody, was effective in children with systemic juvenile idiopathic arthritis, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Washington, DC. Tocilizumab blocks the action of a protein, called interleukin 6, or IL-6, which promotes inflammation.

About 1 child in every 1,000 develops some type of juvenile arthritis. There are several different types of juvenile idiopathic arthritis. All cause joint inflammation and begin before the age of 16, but otherwise have distinct symptoms and complications and may require different approaches to treatment. Systemic onset JIA affects about 10 percent of children with arthritis. It begins with a recurrent fever that can be 103 ° F or higher, often accompanied by a pink rash that comes and goes. Systemic onset JIA may cause inflammation of the internal organs as well as the joints.

In this phase III clinical trial of systemic JIA (abstract 722), 56 children (35 female, 21 male, mean age 8.3 years old) with systemic juvenile idiopathic arthritis with an inadequate response to oral steroids initially received 8mg/kg of tocilizumab intravenously every other week for six weeks. 38 (68%) of the children had an improvement rate of 70%, while more than 85% had an improvement rate of 50%. At the end of this period, 43 patients met the responder criteria (at least a 30% improvement as measured by low C-reactive protein levels). These 43 patients proceeded to the double-blind period of the study and were randomized to receive either 8 mg/kg of tocilizumab or placebo every other week for 12 weeks. Among the 43 patients who agreed to continue into the blinded portion of the study, 82.6% of those randomized to placebo withdrew because of a flare during the next 12 weeks, versus only 20% of those randomized to tocilizumab.

Most patients had an immediate resolution of their fever and had significantly improved laboratory parameters during the treatment period (leukocytosis, thrombocytosis, anemia, high ESR and CRP). Only one patient in each group was withdrawn from the study due to an adverse event ( one was withdrawn due to the onset of EB virus infectious mononucleosis and the other due to varicella zoster virus, or chicken pox).

A second study (abstract #286) evaluated tocilizumab in two other kinds of JIA, polyarticular onset (affecting five or more joints), and oligoarticular onset (affecting fewer than five joints) . Nineteen patients (17 with polyarticular onset; 2 with oligoarticular onset), mean age 11.6 years, were enrolled in this prospective, open-label, multi-center study. All 19 patients received 8 mg/kg tocilizumab every 4 weeks for 12 weeks. Concomitant therapies with anti-TNF biologics, DMARDs and immunosuppressants were not allowed during the study. Disease activity was assessed every 4 weeks by a composite of disease measures, including active joints, function, ESR, and overall patient and physician disease assessment.

At week 12, 11 (57.9%) patients demonstrated 70% improvement in the composite disease parameters, and 18 (94.7%) demonstrated 50% improvement. The most common adverse events were minor liver test and blood lipid abnormalities and upper respiratory tract infections. Two patients were hospitalized for gastroenteritis and one patient was hospitalized for sensory disturbance. These events resolved with medication or spontaneously.

Polyarticular JIA, which involves five or more joints, affects about half of all children with arthritis. Oligoarticular or pauciarticular arthritis affects fewer than 5 joints.

“ While these data are preliminary and require further confirmation, they do suggest that this therapy may offer another important treatment option for children with JIA,” said Shumpei Yokota, MD, Yokohama City University School of Medicine and an investigator in both studies. “Tocilizumab is particularly promising for those children with severe systemic JIA who have failed other available therapies.”

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR’s annual meeting, see www.rheumatology.org/annual.

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Editor’s Notes: Dr. Yokota will present this research during the ACR Annual Scientific Meeting at the Washington Convention Center: abstract #722 from 4:30 – 6:00 pm EST on Sunday, November 12, 2006 in Room 152, and abstract #286 from 9:00 – 11:00 am EST on Sunday, November 12, 2006, in Exhibit Hall A-B. He will be available for media questions and briefing at 1:30 pm EST on Monday, November13, in the on-site Press Conference Room 209C.


Presentation Number: 722

Rapid Improvement of Signs and Symptoms Associated with Systemic Juvenile Idiopathic Arthritis (sJIA) by Interleukin-6 (IL-6) Blockade - Results from a Tocilizumab sJIA Phase III Clinical Trial

Shumpei Yokota 1, Tomoyuki Imagawa 1, Masaaki Mori 1, Syuji Takei 2, Yoshifumi Kawano 2, Naomi Iwata 3, Minako Tomiita 4, Mari Miyoshi 5, Yuko Aihara 6, Takuji Murata 7, Daiki Abukawa 8, Norihiro Nishimoto 9, Tadamitsu Kishimoto 9. 1Departmet of Pediatrics, Yokohama City University School of medicine, Yokohama, Japan; 2Kagoshima University School of Medicine, Kagoshima, Japan; 3Aichi Children's Health and Medical Center, Obu, Japan; 4Chiba University, Chiba, Japan; 5Kobe Children's Hospital, Kobe, Japan; 6Yokohama City University Medical Center, Yokohama, Japan; 7Osaka Medical College, Takatsuki, Japan; 8Miyagi Children's Hospital, Sendai, Japan; 9Osaka University, Osaka, Japan

Purpose: It has been shown in previous clinical trials that IL-6 is critical in the pathogenesis of sJIA and that IL-6 blockade with tocilizumab is effective in controlling the disease. A double-blind, randomized, placebo-controlled Phase III trial with tocilizumab in sJIA has been performed to confirm the efficacy and safety.

Methods: Patients with sJIA diagnosed according to ILAR criteria with CRP > 1,5mg/dl and inadequate response to oral steroids were enrolled in this prospectively randomized, double-blind, multicenter study in Japan. Initially all patients received 8mg/kg of tocilizumab intravenously every other week for 6 weeks. At the end of this period, patients who met the responder criteria (at least JIA30 response and CRP<0.5mg/dl) were allowed to proceed to the double-blind period and randomized to receive either 8mg/kg of tocilizumab or placebo every other week for 12 weeks. If patients failed to maintain the responder criteria during the double blind period, they were withdrawn from the study and received active conventional treatment outside the study.

Results: Fifty-six patients entered the 6-week open-label period. At baseline, mean age was 8.3 years, mean duration of sJIA was 4.5 years and mean steroid dose was 0.51mg/kg/day. JIA30, JIA50 and JIA70 responses were achieved in 51 (91.1%), 48 (85.7%) and 38 (67.9%) of patients respectively at the end of the open-label period. Most patients with high spiking fever had an immediate resolution after tocilizumab therapy. Leukocytosis, thrombocytosis, anemia, elevated CRP and ESR also improved significantly. Forty-three patients met the responder criteria and agreed to be randomized to receive either tocilizumab (n=20) or placebo (n=23) in the double-blind period. Four of 20 tocilizumab patients (20.0%) were withdrawn from the study, as compared with 19 of 23 placebo patients (82.6%) (P<0.001). Only one patient in each group was withdrawn due to an AE. No tuberculosis was observed.

Conclusions: Treatment with tocilizumab, 8mg/kg every other week, resulted in rapid and substantial improvement in children with sJIA and was generally well tolerated over a period of up to 18 weeks. The long-term efficacy and tolerability of tocilizumab are currently being investigated in an extension study.

Disclosure Block: S. Yokota, None; T. Imagawa, None; M. Mori, None; S. Takei, None; Y. Kawano, None; N. Iwata, None; M. Tomiita, None; M. Miyoshi, None; Y. Aihara, None; T. Murata, None; D. Abukawa, None; N. Nishimoto, None; T. Kishimoto, None.

Presentation Number: 286

Efficacy and Safety of tocilizumab, an Anti-IL-6 Receptor Monoclonal Antibody, in Patients with Polyarticular or Oligoarticular Onset Juvenile Idiopathic Arthritis

Tomoyuki Imagawa 1, Masaaki Mori 1, Syuji Takei 2, Yoshifumi Kawano 2, Naomi Iwata 3, Mari Miyoshi 4, Takuji Murata 5, Norihiro Nishimoto 6, Tadamitsu Kishimoto 6, Shumpei Yokota 1. 1Yokohama City University School of Medicine, Yokohama, Japan; 2Kagoshima University School of Medicine, Kagoshima, Japan; 3Aichi Children's Health and Medical Center, Obu, Japan; 4Kobe Children's Hospital, Kobe, Japan; 5Osaka Medical College, Takatsuki, Japan; 6Osaka University, Osaka, Japan

Purpose: This study was conducted to evaluate the efficacy and safety of tocilizumab in polyarticular course juvenile idiopathic arthritis (pJIA) patients with polyarticular or oligoarticular onset but not those with systemic onset.

Methods: Patients with pJIA diagnosed as polyarticular or oligoarticular onset according to the ILAR criteria were enrolled in this prospective, open-label, multi-center study. Eligible pJIA patients received 8 mg/kg tocilizumab every 4 weeks for 12 weeks. Concomitant therapies with anti-TNF biologics, DMARDs and immunosuppressants were not allowed during the study. Disease activity was assessed every 4 weeks by determining JIA core set variables. Patients who achieved 30% or more improvement of JIA core set were considered as responders.

Results: Of 19 pJIA patients enrolled, 17 and 2 were polyarticular and oligoarticular onset, respectively. The mean age was 11.6 years with the mean disease duration of 5.3 years. IL-6 level was elevated at baseline with the mean value of 33.6 pg/mL (normal range <4 pg/mL). All 19 patients received 8 mg/kg tocilizumab every 4 weeks and completed the 12-week study period. At week 12, the JIA core set 30%, 50% and 70% improvement were achieved in 18 (94.7%), 18 (94.7%) and 11 (57.9%) patients, respectively. Consistent improvement was observed in each core set variables. The most common adverse events (AEs) were infections, predominantly mild upper respiratory infections. Mild increases in liver enzyme and lipids were observed although the values remained nearly within normal range. Three patients experienced hospitalized AEs, gastroenteritis in two and sensory disturbance in one. These events resolved with medication or spontaneously. No tuberculosis was observed.

Conclusions: Consistent with improvements observed in adult RA patients, tocilizumab demonstrated significant improvements in signs and symptoms associated with pJIA of polyarticular or oligoarticular onset, and was generally well-tolerated. These data suggested that targeted blockade of IL-6 signal represent an effective approach to the treatment of pJIA.