FRI0042 THE SAFETY OF KINERET™ (ANAKINRA) IN HIGH-RISK PATIENTS
M. Schiff, S. Hartman, G. Devittorio, T. Liu, S. Fletcher, A. Solinger

Anakinra is an interleukin-1 receptor antagonist (IL-1ra) recently approved for treatment in patients with rheumatoid arthritis (RA). The purpose of this study was to assess the safety of anakinra in RA patients having at least one high-risk comorbidity.

Methods: 1399 RA patients treated with either daily subcutaneous injections of anakinra or placebo in a double-blind, placebo-controlled safety study were retrospectively assessed for a history of cardiovascular events (CHF, CAD), pulmonary events (asthma, COPD, pneumonia), infections (opportunistic or chronic infections), CNS-related events (demyelination events, stroke), diabetes, malignancies, and renal impairment. Incidence of serious adverse events (SAE), serious infectious event (SIE), and infectious event (IE) were assessed in each category, as well as an overall incidence rate. No patients with uncontrolled medical condition were included in the analysis. Patients were allowed to continue stable doses of NSAIDS, oral corticosteroids, and DMARDs.

Results: The overall rate of IE was 41.2% (460 of 1116) in patients treated with anakinra and 43.5% (123 of 283) in patients treated with placebo. The following table gives a further breakdown of the results for SIE and SAE.

Summary: These data show that RA patients with >1 comorbid condition receiving treatment with anakinra do not have an increased risk of IEs or SAEs. A modest increase in SIEs is noted with the use of anakinra. Although this increase was not significantly associated with a specific comorbidity, asthma showed the strongest association.

Editorial Comments: This and other large safety trials with biologic agents have focused on their safety in conjunction with conventional DMARDs. In addition, this study examined safety in RA patients with comorbid illnesses as well, albeit retrospectively. It will be interesting to determine whether asthma is a risk factor for serious infections with other biologic agents.

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FRI0083 SAFETY OF COMBINATION THERAPY WITH KINERET™ (ANAKINRA) AND ETANERCEPT IN PATIENTS WITH RHEUMATOID ARTHRITIS
M. Schiff, K. Bulpitt, A. Weaver, F. Kazazi, T. Joh, R. Newmark

(See ACR 2001 Highlights)

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OP0090 WEEKLY TREATMENT WITH IL-1 TRAP IS WELL TOLERATED AND IMPROVES ACR CRITERIA IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS
H.P. Guler, J.R. Caldwell, R.M. Fleischman, S.B. Cohen, A.J. Kivitz, R.M. Levy, T. Littlejohn, H. McIlwain, H. Offenberg, J. Papadopoulos, N. Stahl

A "cytokine trap" is a single recombinant IgG Fc fusion molecule containing the extracellular domains of two distinct receptors for a single cytokine. This fusion protein mimics the natural cell surface receptor and binds the target cytokine with very high affinity, thereby trapping the cytokine to block its activity. The IL-1 Trap is an Fc fusion protein consisting of both the IL-1 Type I Receptor and the IL-1 Receptor Accessory Protein, and binds both IL-1b and IL-1a with very high affinity (dissociation constants KD = 1-2 pM), yet binds IL-1ra more weakly (KD = 43 pM). The purpose of this study was to assess its safety and tolerability in humans.

Methods: 82 patients with active rheumatoid arthritis (RA) participated in this double blind, placebo controlled trial. Patients received IL-1 trap at a dose of 50 mcg/kg (n=5), 100 mcg/kg (n=5), 200 mcg/kg (n=18), 400 mcg/kg (n=16), 800 mcg/kg (n=20), or placebo (n=20) for 6 weeks. Concomitant treatment with methotrexate or prednisone <10 mg/day was allowed.

Results: Other than short-lived stinging at the injection site, adverse events in patients treated with IL-1 trap were similar to those in patients treated with placebo. No antibodies to IL-1 trap developed over the 9 weeks of observation. The terminal half-life of the IL-1 Trap was 7.5 days in the 400 and 800 mcg/kg dose groups. Cmax at the highest dose averaged 3.5 mcg/mL and accumulated to 10.8 mcg/mL over the 6 week treatment. Joint counts and CRP levels improved in a dose dependent fashion with some patients meeting the ACR 20 criteria for improvement over 6 weeks.

Summary: IL-1 Trap was well tolerated up to 800mcg/kg weekly and appears to reduce symptoms of RA, thereby having possible therapeutic potential.

Editorial Comments: This is an interesting novel approach to inhibit IL-1. This IL-1 TRAP fusion protein has a longer half-life than IL-1ra (Kineret™), but it is too early to tell whether it will be more efficacious. Its picomolar affinity constant indicates high potency in vitro. We will look forward to Phase II and III studies with this agent.

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FRI0098 RESULTS OF A PHASE 1 SAFETY AND PHARMACOKINETIC STUDY OF INTERLEUKIN-1 RECEPTOR IN RHEUMATOID ARTHRITIS
J. Caldwell, H. Offenberg, J. Agosti, T. DeVries, D. Wang, M. Hearell, D. Burge

This was a phase I dose-escalation, safety and pharmacokinetic study of recombinant human interleukin-1 receptor type II (IL-1RII) in patients with rheumatoid arthritis. Because IL-1RII binds IL-1 and inhibits its activity, IIL-1RII may prove beneficial in treating inflammatory conditions such as rheumatoid arthritis (RA).

Methods: 28 patients were followed for 28 days after receiving a single dose of IL-1RII (0.015. 0.05, 0.15, 0.5, 1.5, or 3.0 mg/kg SC or 0.015 mg/kg IV; n=4 for each dose).

Results: No serious adverse events, injection site reactions, or toxicities were seen in any of the patients. No patients developed antibodies. Pharmacokinetic analysis demonstrated a mean (SD) serum half-life of 58.0 (14.8) hours, mean (SD) AUC(0-inf) per mg dose of 3.20 (1.44) nghr/mL and mean bioavailability of 65.3%. The following was observed:

• 1 patient developed transient elevation of blood pressure when blood pressure medications were not taken
• 2 patients developed grade 1 influenza
• 1 patient with preexisting diabetes mellitus on oral hypoglycemics developed a nonfasting grade 3 blood sugar elevation (not related to study drug)
• 1 patient with preexisting lymphopenia developed a grade 3 lymphopenia during study

Summary: Based on these initial data, IL-1RII in doses up to 3.0 mg/kg appears to be well-tolerated in RA patients.

Editorial Comments: Clinical trials with this IL-1 inhibitor are planned. Its longer half-life gives it an advantage over IL-1ra (Kineret™) but its relative efficacy is unknown at this time.

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