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Anakinra (Kineret® ™) FDA Approved for Use in Rheumatoid Arthritis

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Anakinra (Kineret® ™) FDA Approved for Use in Rheumatoid Arthritis

November 2001

On November 14, 2001 the Food and Drug Administration (FDA) approved Amgen's new product anakinra, a recombinant form of the naturally occurring interleukin-1 receptor antagonist (IL-1ra). This product is indicated for use in patients with moderate to severe rheumatoid arthritis who have not had an adequate response to conventional DMARD therapy. The drug may be used as monotherapy or in combination with methotrexate or other DMARDs. Anakinra is a biologic response modifier that acts by antagonizing the biologic effects of IL-1.

IL-1 is a proinflammatory cytokine. It is produced by numerous cell types (i.e., macrophages, synoviocytes, endothelial cells, chondrocytes, osteoclasts) and is found in excess in the serum, synovial fluid and synovial tissues of patients with RA and other inflammatory arthritides. In animal models, IL-1 is capable of mediating and amplifying destructive inflammatory arthritis. In RA, serum and synovial IL-1 levels have been correlated with disease severity. Like tumor necrosis factor (TNF), IL-1 is a pleiotropic cytokine that has numerous biologic activities, including: activation of T and B cells; induction of other cytokines and chemokines (e.g., IL-6, TNF, IL-8); release of degradative enzymes (collagenase, stromelysin, metalloproteinases) and other inflammatory mediators (nitric oxide, cyclooxygenase 2, PAF); synoviocyte proliferation; expression of adhesion molecules (on vascular endothelium) and RANK ligand; resorption of bone and degradation of cartilage. IL-1ra is a counter-regulatory cytokine that rises in an acute phase fashion in response to IL-1 production and competes with IL-1b for binding to type I IL-1 receptors. Thus, anakinra is a competitive inhibitor of IL-1 and must be present in large amounts to abrogate the biologic effects of IL-1.

Human IL-1ra has been isolated from human monocytes and has been cloned and expressed in E. coli. Anakinra is a nonglycosylated, recombinant human IL-Ra and differs from endogenous human IL-1ra by the addition of an N-terminal methionine. It binds with the same avidity as native IL-1ra and IL-1b. It is 153 amino acids and 17.3 kD in size and has a biologic half-life of 4-6 hours. It is self-administered by patients as a daily subcutaneous injection using prefilled 100 mg syringes.

Anakinra has been studied in several RA clinical trials and has been shown to have a satisfactory efficacy and safety profile. FDA approval has been based on 5 separate randomized placebo-controlled clinical trials involving 2932 RA patients. In these trials the ACR20 response rates were 38-42%. ACR50 and ACR70 response rates ranged from 11-24% and 1-10%, respectively. A monotherapy trial of anakinra in 472 RA patients showed significant reduction in radiographic progression after 24 and 48 weeks of therapy1. In these trials, withdrawal rates ranged from 12.1-27.1%, with more withdrawals for adverse events than lack of efficacy. In these clinical trials both fixed doses (75 or 150 mg qd) or adjusted doses (1 or 2 mg/kg/d) were studied. The recommended dose will be 100 mg qd, administered subcutaneously using prefilled 100 mg syringes. Although higher doses have been studied, dose related benefits were not uniformly observed and more frequent injection site reactions (ISRs) have been seen at higher doses.

Nearly 1500 patients have received anakinra 100 mg qd for between 6-12 months. Over 60 patients have been on anakinra for 4 years or longer. During clinical trials, patient compliance was observed to be >95%. The primary adverse event noted in clinical trials was ISRs. These were usually observed in the first 4 weeks, disappeared within days to weeks and required patient reassurance and no further treatment. ISRs were usually described as erythema, rash, urticaria, ecchymoses, with either no complaint or complaint of dysesthesia or mild pruritis. These were described as mild-moderate in nearly 95% of patients. Other infrequent adverse reactions included mild reductions in neutrophil counts, headache and an increase in URIs. Anakinra was originally studied in sepsis. While it did not show a protective effect, it was not associated with increased infectious risk or mortality. Infections were infrequently seen with anakinra. The serious infection (according to FDA definition of serious adverse event) was 1.8% vs. 0.7% for those receiving 100 mg/d vs. placebo respectively. Pneumonia (N=14) was the most common serious infection noted. Analysis of all patients revealed a slightly higher rate of pulmonary infections for those with asthma and COPD - thus caution should be exercised when using this agent in such patients. . Therapy with anakinra should not be initiated in patients who have active infections. The combined use of anakinra and a TNF inhibitor was tested in a small pilot study of 58 RA patients who had active synovitis despite etanercept therapy and were then given anakinra 100 mg qd along with etanercept 25 mg BIW. While many of these patients did improve, 4 of 58 (7%) had serious infections (2 cellulitis, 2 pneumonia). The package insert warns that the combined use of TNF inhibitors and anakinra "should only be done with extreme caution and when no satisfactory alternatives exist". Other larger controlled trials of anakinra plus etanercept are in progress. To date there have been no reports of mycobacterial or other opportunistic infections in clinical trial patients receiving anakinra in the USA or Europe.

Patients will have the option of self-injecting 100 mg prefilled syringes or loading these into a specially designed injector device, called Simpleject™. This prescription device will be provided to rheumatologists along with a patient education kit and is designed to work with anakinra 100 mg prefilled syringes and will not work with other injectable medicines (ie, etanercept). Patients will also be given travel packs and are advised to keep anakinra refrigerated at 2-8oC (36-48oF) until planned use at room temperature.

John J. Cush2, Arthur F. Kavanaugh3, Eric L. Matteson
Hotline Editors
November 2001


1. Jiang, Y et al. Arthritis Rheum 2000 May; 43(5): 1001-9
2. Dr. Cush is a paid consultant and speaker for Amgen.
3. Dr. Kavanaugh is a paid consultant for Amgen

November 2001

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