Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE Effects of Gevokizumab on Glycemia and Inflammatory Markers in Type 2 Diabetes 1 3 CLAUDIA CAVELTI-WEDER, MD HANY ZAYED, PHD (IL-1Ra), was tested in a placebo-controlled 1 4 ANDREA BABIANS-BRUNNER, MD ALAN M. SOLINGER, MD 1 5 study of 70 patients (5). At 13 weeks of CORNELIA KELLER, MD THOMAS MANDRUP-POULSEN, MD, PHD 2 6 treatment, glycated hemoglobin was signif- MARC A. STAHEL, MD CHARLES A. DINARELLO, MD 2 1 icantly improved as a result of enhanced MALAIKA KURZ-LEVIN, MD MARC Y. DONATH, MD b-cell secretory function. Of interest, some improvement promoted by IL-1b blockade lasted for at least 39 weeks follow- OBJECTIVEd b Metabolic activation of the innate immune system governed by interleukin (IL)-1 ing treatment withdrawal (6). More re- contributes to b-cell failure in type 2 diabetes. Gevokizumab is a novel, human-engineered mono- clonal anti–IL-1b antibody. We evaluated the safety and biological activity of gevokizumab in cently, IL-1Ra also was shown to improve patients with type 2 diabetes. insulin secretion in prediabetic patients (7). This indicates the disease-modifying po- RESEARCH DESIGN AND METHODSdIn a placebo-controlled, dose-escalation tential of this therapy (8). study, a total of 98 patients were randomly assigned to placebo (17 subjects) or gevokizumab Although the results obtained with (81 subjects) at increasing doses and dosing schedules. The primary objective of the study was to fi IL-1Ra in patients with type 2 diabetes are evaluate the safety pro le of gevokizumab in type 2 diabetes. The secondary objectives were to assess encouraging, IL-1Ra has characteristics pharmacokinetics for different dose levels, routes of administration, and regimens and to assess that make it unsuitable for the treatment biological activity. of type 2 diabetes, such as its short half-life RESULTSdThe study drug was well tolerated with no serious adverse events. There was one and injection-site reactions (9). It would hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of have to be taken on a daily basis to maintain gevokizumab was consistent with that for a human IgG2, with a half-life of 22 days. In the adequate suppression of IL-1b. Moreover, combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo- the amount of IL-1Ra required would make correcteddecreaseinglycatedhemoglobinwas0.11,0.44,and0.85%after1,2(P =0.017),and3 P treatment an expensive option. Of impor- ( = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin tance, an anti–IL-1 strategy that spares sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines. IL-1a may offer safety benefits. Therefore, CONCLUSIONSdThis novel IL-1b–neutralizing antibody improved glycemia, possibly via specifically reducing IL-1b activity with restored insulin production and action, and reduced inflammation in patients with type 2 longer-lasting agents would provide a diabetes. This therapeutic agent may be able to be used on a once-every-month or longer therapeutic improvement in terms of sus- schedule. tained inhibition of IL-1b–mediated islet- associated inflammation. Diabetes Care – 35:1654 1662, 2012 Gevokizumab is a recombinant human- engineered monoclonal antibody that nset of type 2 diabetes occurs when to a pathological activation of the innate binds and neutralizes human IL-1b pancreatic b-cells fail to adapt to the immune system by metabolic stress and is with a Kd of 0.3 pmol/L (10). The predicted O – increased insulin demand caused governed by interleukin (IL)-1 signaling circulating half-life of the antibody was 22 by insulin resistance. Morphological and (1–4). 25 days. The Fc of gevokizumab is the IgG2 therapeutic intervention studies have un- Based on the above-described islet isotype, which unlike IgG1 Fc does not ac- covered an inflammatory process in islets inflammation with a predominant role for tivate the FcRIII on macrophages and other of patients with type 2 diabetes character- IL-1b, we initiated clinical trials of IL-1 myeloid cells, thereby reducing the proba- ized by the presence of cytokines, im- antagonism in type 2 diabetes. In a proof- bility of antibody-dependent cell-mediated mune cells, b-cell apoptosis, amyloid of-concept study, the naturally occurring cytotoxicity. In this study, we evaluated the deposits, and fibrosis.Thisisattributed antagonist of IL-1b,IL-1receptoragonist safety, pharmacokinetics, and diabetes- and inflammation-related parameters of ccccccccccccccccccccccccccccccccccccccccccccccccc gevokizumab in patients with type 2 diabetes. From the 1Department of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland; the 2Department of Ophthalmology, University Hospital Zurich, Zurich, Switzerland; the 3Department of Biostatistics, XOMA, Berkeley, California; the 4Department of Clinical Development, XOMA, Berkeley, RESEARCH DESIGN AND 5 California; the Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark, METHODSdThis first-in-humans, and the Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; and the 6Department of Medicine, University of Colorado Denver, Aurora, Colorado. randomized, placebo-controlled, dose- Corresponding author: Marc Y. Donath, [email protected]. escalation study was carried out concur- Received 15 November 2011 and accepted 27 March 2012. rently in the U.S. and Switzerland. The U.S. DOI: 10.2337/dc11-2219. Clinical trial reg. no. NCT00541983, clinicaltrials.gov. arm of the study included 68 subjects (56 A slide set summarizing this article is available online. © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly in the gevokizumab group and 12 in the cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ placebo group) and took place between licenses/by-nc-nd/3.0/ for details. September 2007 and June 2009. The Swiss 1654 DIABETES CARE, VOLUME 35, AUGUST 2012 care.diabetesjournals.org Cavelti-Weder and Associates arm of the study included 30 subjects (25 aminotransferase/alanine aminotransferase intravenous stimulation tests of C-peptide in the gevokizumab group and 5 in the .2 3 upper limit of normal; alkaline phos- release were included. A glucose stimula- placebo group) and took place between phatase .2 3 upper limit of normal; tion test was performed at baseline and at November 2007 and July 2009. XOMA positive test for GAD65 or insulinoma- 4 and 13 weeks to assess b-cell function (U.S.), the manufacturer of gevokizumab, associated protein 2 autoantibodies; and insulin production/reserve. Subjects sponsored the study. known HIV antibody positivity, hepatitis B ingested 75 g glucose and were sampled The eligibility criteria of both arms of surface antigens, and/or hepatitis C anti- for plasma glucose and C-peptide mea- the study were similar. Patients were re- bodies; history or evidence of thyroid abnor- surements at –10, 0, 30, 60, 90, and 120 quested to continue stable doses of baseline malities, including active hyperthyroidism min. Immediately at the end of the oral antidiabetes treatments (metformin, sulfo- needing medication; abnormal T3, T4, glucose tolerance test, an intravenous in- nylureas, and/or insulin) and were asked thyroglobulin, or thyroid-stimulating hor- jection of 0.3 g glucose/kg body wt, 0.5 mg not to change their diet and exercise mone levels; infectious disease (C-reactive glucagon, and 4.5 g arginine was adminis- habits during the study. Both arms of the protein [CRP] .30 mg/L), fever, or infec- tered. Blood then was sampled at 0, 3, 6, 9, study tested single intravenous doses of tion requiring treatment with antibiotics and 12 min. The patients were asked to gevokizumab at the same five-dose levels within 3 weeks; history of recurrent infec- forgo their antidiabetes medication and (0.01, 0.03, 0.1, 0.3, and 1.0 mg/kg). In tion or predisposition to infection; (active fast for 8–9 h prior to the test. Whole- addition, there was a three-part study in the leg or foot ulcer); malignancy within 5 body insulin sensitivity index was calculat- U.S. arm that tested a single intravenous years prior to study entry other than car- ed as 10,000/square root of [fasting glucose dose of 3.0 mg/kg (part 1), a single sub- cinoma in situ of the cervix or adequately (mmol/L) 3 fasting insulin (pmol/L) 3 cutaneous dosing at three dose levels (part treated, nonmetastatic squamous or basal (mean glucose {mmol/L} 3 mean insulin 2), and multiple subcutaneous dosing at two cell carcinoma of the skin; history of severe {pmol/L} during the oral glucose tolerance dose levels (part 3) (Fig. 1A). The follow-up allergic or anaphylactic reactions to human- test)] (12). of patients was 2 months in the U.S. arm and ized or murine monoclonal antibodies; his- 3 months in the Swiss arm. Randomization tory of tuberculosis, positive purified Whole-blood cultures for ex vivo was performed with the use of a common, protein derivative test, or active atopic dis- cytokine production central, computer-generated system with ease requiring medication; asthma; immu- Heparinized blood was obtained before permutated blocks of six schedules. nodeficiency; history or symptoms of a and on days 1, 7, and 28 after the admin- Throughout the course of the study, demyelinating disease; clinically significant istration of gevokizumab. At the same time, treatment assignment was blinded to study diabetic macular edema and/or proliferative blood was sent for routine hematology. A subjects and investigators but not to the diabetic retinopathy by history or fundo- total of 250 mLofbloodwereaddedto sponsor (XOMA). The sponsor maintained scopy; use of a therapeutic monoclonal 1.5-mL sterile cryotubes (Fisher) con- blinding in all communications with inves- antibody within 90 days; participation in taining 750 mL of RPMI (Grand Island) tigators and other site personnel.