Dorothy McCabe

Treatment of rheumatoid arthritis with recombinant human interleukin‐1 receptor antagonist

OBJECTIVE To evaluate the efficacy and safety of interleukin-1 receptor antagonist (IL-1Ra) in patients with rheumatoid arthritis (RA). METHODS Patients with active and severe RA (disease duration <8 years) were recruited into a 24-week, double-blind, randomized, placebo-controlled, multicenter study. Doses of nonsteroidal antiinflammatory drugs and/or oral corticosteroids (< or =10 mg prednisolone daily) remained constant throughout the study. Any disease-modifying antirheumatic drugs that were being administered were discontinued at least 6 weeks prior to enrollment. Patients were randomized to 1 of 4 treatment groups: placebo or a single, self-administered subcutaneous injection of IL-1Ra at a daily dose of 30 mg, 75 mg, or 150 mg. RESULTS A total of 472 patients were recruited. At enrollment, the mean age, sex ratio, disease duration, and percentage of patients with rheumatoid factor and erosions were similar in the 4 treatment groups. The clinical parameters of disease activity were similar in each treatment group and were consistent with active and severe RA. At 24 weeks, of the patients who received 150 mg/day IL-1Ra, 43% met the American College of Rheumatology criteria for response (the primary efficacy measure), 44% met the Paulus criteria, and statistically significant improvements were seen in the number of swollen joints, number of tender joints, investigators assessment of disease activity, patients assessment of disease activity, pain score on a visual analog scale, duration of morning stiffness, Health Assessment Questionnaire score, C-reactive protein level, and erythrocyte sedimentation rate. In addition, the rate of radiologic progression in the patients receiving IL-1Ra was significantly less than in the placebo group at 24 weeks, as evidenced by the Larsen score and the erosive joint count. IL-1Ra was well tolerated and no serious adverse events were observed. An injection-site reaction was the most frequently observed adverse event, and this resulted in a 5% rate of withdrawal from the study among those receiving IL-1Ra at 150 mg/day. CONCLUSION This study confirmed both the efficacy and the safety of IL-1Ra in a large cohort of patients with active and severe RA. IL-1Ra is the first biologic agent to demonstrate a beneficial effect on the rate of joint erosion.

A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: Radiologic progression and correlation of genant and larsen scores

OBJECTIVE To evaluate radiographic progression and the relationship of radiologic scores obtained by the Genant and Larsen methods in a clinical trial of recombinant human interleukin-1 receptor antagonist (IL-1Ra). METHODS Patients with rheumatoid arthritis (RA) were randomized into 4 groups: placebo (n = 121) or IL-1Ra at a daily dosage of 30 mg (n = 119), 75 mg (n = 116), or 150 mg (n = 116). Hand radiographs obtained at baseline, 24 weeks, and 48 weeks were scored using both methods. RESULTS At 24 weeks, by the Genant method, there was significant reduction in the score for progression of joint space narrowing (JSN) and the total score (a combination of erosion and JSN) in all treatment groups. Least-squares mean changes in the Genant erosion score from baseline to 24 weeks were significantly reduced after treatment with IL-1Ra at 30 mg/day and for all IL-1Ra treatment groups combined. The changes corresponded to a reduction of 38% in erosion, 58% in JSN, and 47% in total score. Patients treated with IL-1Ra at 75 mg/day had a significant reduction in the Larsen erosive joint count (LEJC), and all IL-1RA-treated groups combined showed a 45% reduction. Correlations (r) between the Genant total and Larsen scores were 0.84 at baseline, 0.83 at week 24, and 0.83 at week 48 (P < 0.0001); correlations between the Genant erosion score and the LEJC were 0.83 (P < 0.0001) at all visits; correlations between the Genant total and the Larsen scores were 0.32 and 0.49 (P < 0.0001) for progression from baseline to week 24 and from baseline to week 48, respectively; correlations between the Genant erosion score and the LEJC were 0.36 and 0.41 (P < 0.0001) for progression to weeks 24 and 48, respectively. CONCLUSION IL-1Ra reduced radiologic progression of RA. Scores by the 2 methods correlated strongly for each individual time point, but much less strongly for assessments of disease progression.

Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis: comparison of efficacy in animal models with human clinical data.

OBJECTIVE To determine the role of interleukin-1 receptor antagonist (IL-1Ra) in rat adjuvant arthritis and rat type II collagen-induced arthritis, and to compare the efficacy in rat models with that seen in human clinical trials of IL-1Ra. METHODS Rats with developing adjuvant arthritis or established collagen-induced arthritis were treated with IL-1Ra by continuous infusion in order to determine and maintain efficacious blood levels of this IL-1 inhibitory protein in the rats for comparison with human clinical data. The effects of treatment in the rats were monitored by sequential caliper measurement of the ankle joints, determination of final paw weights, and histologic evaluation with particular emphasis on bone and cartilage lesions. The effects of IL-1Ra on joint swelling and radiographic bone damage in patients with rheumatoid arthritis (RA) in a 6-month trial were compared with the findings in rats. RESULTS Dramatic differences in the profile of IL-1Ra activity were seen between the 2 groups of rats. Modest antiinflammatory effects were observed in the adjuvant arthritis rats treated with IL-1Ra. However, marked inhibition of bone resorption occurred, even at doses with which antiinflammatory activity was not seen. In contrast, IL-1Ra treatment of rats with established collagen-induced arthritis resulted in nearly complete suppression of all aspects of the disease when adequate blood levels of IL-1Ra were maintained. Treatment of RA patients with IL-1Ra (150 mg daily) resulted in modest inhibition of joint swelling and inhibition of radiographic progression of bone lesions. CONCLUSION IL-1 appears to be of major importance in mediating the bone resorption that occurs in rat adjuvant arthritis, but is less important in the pathogenesis of periarticular inflammation in this disease. In contrast, IL-1 is of major importance in mediating all aspects of disease progression in rat collagen-induced arthritis. Similar to the response in adjuvant arthritic rats, RA patients treated with IL-1Ra showed only modest antiinflammatory activity, but had evidence of inhibition of progression of bone resorption. However, a comparison of the plasma levels of IL-1Ra in humans and rats suggests that the optimal level of dosing for continuous saturation of IL-1 receptors may not have been achieved in humans, although this was achieved in the rat studies.

Effects of interleukin-1 receptor antagonist in a slow-release hylan vehicle on rat type II collagen arthritis

AbstractPurpose. To determine the effect of hylan fluid (HA), a model slow release vehicle on the pharmacokinetic profile and efficacy of interleukin-1 receptor antagonist (IL-lra) in rats with established type II collagen arthritis. Methods. Female Lewis rats with type II collagen arthritis were treated daily, every other day or every third day with single subcutaneous (sc) injections of IL-lra formulated in HA and the effects on arthritis determined. Results were compared to those obtained with IL-lra in citrate buffered saline with EDTA and polysorbate (CSEP). Sequential blood levels were determined in rats injected sc with IL-lra in CSEP or HA. Results. Incorporation into HA led to slower release of IL-lra into the bloodstream and maintained therapeutic blood levels of IL-lra for a longer time compared to the IL-lra/CSEP formulation. Single daily sc doses of 100 mg/kg IL-lra in CSEP were ineffective in type II collagen arthritis. By contrast, once per day dosing of 100 mg/kg IL-lra in HA provided 78% inhibition of paw swelling. Every other day dosing with 100 mg/kg IL-lra in HA resulted in 62% inhibition. IL-lra (100 mg/ kg in HA) given every third day provided 19% inhibition of arthritis. Improved efficacy correlated with improved pharmacokinetics. Conclusions. Administration of IL-lra in the slow release vehicle HA improves pharmacokinetics and efficacy in rat type II collagen arthritis.

FRI0036 Population pharmacokinetics (pk) of anakinra in subjects with rheumatoid arthritis (ra)

Background Anakinra is a recombinant interleukin-1 receptor antagonist that reduces signs and symptoms and slows joint destruction in RA patients in clinical trials. Population PK analysis was conducted on data from RA patients treated with anakinra. Objectives The objective was to investigate the effect of covariates such as creatinine clearance (CLcr), body weight (WT), age, and sex, on anakinra PK. Methods Subjects (n = 341) received daily SC injections of anakinra at 30, 75, or 150 mg for 6 months; one plasma sample for anakinra measurement was collected from each subject at baseline, and at weeks 1, 4, 12, 20, and 24 before anakinra administration for that day. Plasma samples were analysed for anakinra levels by an ELISA method. Plasma anakinra data were analysed by nonlinear mixed-effects modelling using NONMEM. “Population” mean PK parameters, intersubject variability in the PK parameters, and residual error were estimated. Results Anakinra PK appeared to be dose independent and was adequately described by a one-compartment model with first-order absorption and elimination. Results showed that anakinra volume of distribution (Vd/F) increased linearly with increasing WT (Vd/F = 0.142 * WT, p < 0.05). Both CLcr and WT were significant predictors of anakinra plasma clearance (CL/F); clearance increased with increasing CLcr and WT (CL/F = 23.0 + 0.343 * CLcr + 0.713 * WT, p < 0.05). The plasma clearance of anakinra was higher in men (164 ± 25 mL/min, n = 79) than in women (144 ± 22 mL/min, n = 262) and higher in younger subjects (< 65 yr, 152 ± 24 mL/min, n = 262) than in older subjects (> 65 yr, 138 ± 23 mL/min, n = 79), these differences could be explained by differences in CLcr and WT. Conclusion Results from population PK analyses confirmed nonclincial and clinical data, which showed the kidney to be a major clearance organ for anakinra.