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1/30/2002

Cytokine Blocker Licensed for Relief of Rheumatoid Arthritis Symptoms

Cheryl A. Thompson

Amgen Inc. received approval from FDA to market anakinra (Kineret [PDF]), a recombinant protein that interferes with the binding of the cytokine interleukin-1 (IL-1) to the IL-1 type-1 receptor. The IL-1 blocker is indicated for the reduction in signs and symptoms of moderately to severely active rheumatoid arthritis in patients age 18 or older whose condition has not responded to therapy with at least one disease-modifying antirheumatic drug.

IL-1 participates in the body's natural responses to inflammatory stimuli. Some of these activities manifest as cartilage degradation and bone resorption. The synovia of patients with rheumatoid arthritis contains an endogenous IL-1-receptor antagonist but at a level insufficient to effectively compete with the increased amount of cytokine generated locally as part of the inflammatory response.

Anakinra is produced by recombinant DNA technology. The protein is identical to an endogenous IL-1-receptor antagonist except for a methionine residue that has been added to the beginning of the amino acid sequence.

FDA made its decision on the efficacy of anakinra on the basis of three randomized, double-blind, placebo-controlled studies involving 1392 adults with active rheumatoid arthritis, 920 of whom had been taking a stable dosage of methotrexate, a disease-modifying antirheumatic drug, for at least eight weeks. These studies excluded patients with an underlying disease, such as asthma or controlled diabetes mellitus, that might predispose them to infection.

Response to therapy was measured with an American College of Rheumatology (ACR) instrument that incorporated the physician's assessment of the number of tender joints, number of swollen joints, and overall disease; the patient's judgment of disability, pain, and overall condition; and serum concentration of C-reactive protein. A score of ACR20 meant that the number of tender and swollen joints had decreased by >20% and that the values for at least three of the five other variables had improved by >20%. Scores of ACR50 and ACR70 were assessed in a manner analogous to ACR20.

Thirty-three percent of the 250 patients who received anakinra 100 mg/day and methotrexate in one of the studies had a score of ACR20 after three months of treatment, compared with 24% of the placebo-treated patients. Patients in the anakinra group were also more likely than the placebo users to have a score of ACR50 or ACR70 after three months.

In the major study that excluded concurrent therapy with a disease-modifying antirheumatic drug, anakinra 75 mg/day yielded response levels similar to the 150-mg/day regimen. Both of these regimens produced response levels similar to that in the study of anakinra 100 mg/day with methotrexate. The product's labeling does not report the specific results from the study in which patients received placebo or one of five dosages of anakinra.

Amgen has agreed to provide FDA the results of studies in which radiograms are used to evaluate anakinra's effect on the progression of patients' rheumatoid arthritis. The recombinant protein is also under investigation in pediatric patients with juvenile rheumatoid arthritis.

Because therapy with anakinra has been associated with the development of serious infections, the product's labeling warns against initiating treatment in patients with an active infection and advises stopping treatment if a serious infection develops. Patients' neutrophil count should be evaluated before starting anakinra therapy, monthly for three months during treatment, and then quarterly for the first year. Particular attention should be given to elderly patients, who in general seem to have a higher incidence of infections than younger people, and to patients with asthma, who seemed to be at higher risk of serious infection during the studies than were placebo users.

Also, on the basis of preliminary data, the product's labeling warns in boldface type that combination therapy with anakinra and a tumor necrosis factor-blocking agent, such as etanercept, be undertaken with extreme caution and only as a last resort. Bacterial pneumonia or cellulitis was diagnosed in 4 of the 58 patients who received anakinra and etanercept for up to 24 weeks; 2 of these patients had an absolute neutrophil count of <1 x 109 cells/L.

A month after receiving word that FDA had approved the licensing of anakinra, Amgen Inc. announced its plan to buy Immunex Corp., the company that produces etanercept, a tumor necrosis factor (TNF)-blocking agent used in the treatment of patients with moderately to severely active rheumatoid arthritis. Although anakinra and etanercept share an indication, anakinra's labeling states that the medication should not be used with a TNF-blocking agent. Or if used together, the combination therapy should be undertaken with extreme caution "and when no satisfactory alternatives exist." FDA has requested the results of an ongoing study of patients with rheumatoid arthritis who are receiving anakinra and etanercept and asked Amgen to conduct a randomized study of patients who would receive anakinra with or without infliximab, another TNF-blocking agent.

The most common adverse events reported during the clinical studies of anakinra 100 mg/day were injection-site reaction (71%), infection (40%), headache (12%), nausea (8%), diarrhea (7%), and abdominal pain (5%).

During therapy with anakinra, which would be expected to alter the body's response to antigens, patients should not receive a live vaccine. The general effect of vaccination in patients receiving anakinra is not known.

In healthy people, anakinra has an absolute bioavailability of 95% after s.c. injection. The maximum plasma concentration of anakinra in patients with rheumatoid arthritis occurs three to seven hours after s.c. injection, and the terminal half-life ranges from four to six hours. In otherwise healthy people with an estimated creatinine clearance of <30 mL/min, the mean plasma clearance of anakinra is 70–75% slower than in those with a normal creatinine clearance.

The recommended dosage of anakinra is 100 mg/day administered by s.c. injection at about the same time each day.

Kineret is supplied in single-use 1-mL glass syringes with 27-gauge needles, with 7 or 28 syringes to a package. Each syringe contains 100 mg of anakinra in 0.67 mL of preservative-free solution, which ranges in appearance from clear and colorless to white. The syringes should be stored at 2–8 degrees C, protected from light, and should not be frozen or shaken.

The packaging includes an insert for patients and caregivers. After use, the syringes and needles should be placed in a puncture-resistant container.