2003 EULAR. Oral presentation today. Sorry if this is repeat.
OP0008 FIRST USE OF A HUMAN MONOCLONAL ANTIBODY AGAINST IL-15 (HUMAX-IL15) IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS (RA): RESULTS OF A DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE I/II TRIAL
B. Baslund1, N. Tvede1, B. Danneskiold-Samsoe2, J. Petersen3, L. J. Petersen3, J. Schuurman4, J. Van de Winkel4, P. Larsson5, G. Panayi6, I. B. McInnes7
1Rheumatology Clinic, TA, The Finsen Centre, Rigshospitalet, Copenhagen, 2Rheumatology Clinic, Frederiksberg Hospital, Frederiksberg, 3, Genmab AS, Copenhagen, Denmark, 4, Genmab BV, Utrecht, Netherlands, 5Rheumatology Clinic, Karolinska Sjukhuset, Stockholm, Sweden, 6Department of Rheumatology, Guy's Hospital, London, 7Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, United Kingdom
Background: IL-15 is a critical innate response cytokine with pleiotropic pro-inflammatory effects. IL-15 is present in RA synovial membrane where it promotes T cell activation / chemokinesis, monocyte cytokine release via T cell cognate interactions, neutrophil and NK cell activation. IL-15 blockade in arthritis models suppresses inflammation. HuMax-IL15 is a fully human IgG1,kappa mAb targeting IL-15.
Objectives: To establish the safety/tolerability profile, host immune reactions, and preliminary efficacy of HuMax-IL15 in patients with active RA failing at least one DMARD.
Methods: HuMax-IL15 was given in dose ascending order (0.15, 0.5, 1, 2, 4 and 8 mg/kg) to 6 cohorts of 5 patients (4:1 active:placebo). Patients with active disease on no other DMARD received HuMax-IL15 by subcutaneous infusions as single dose, and were followed for 28 days. In the absence of dose limiting toxicity by day 28, patients received further four doses at weekly intervals, open label (all active). The 0.15 mg/kg cohort was not extended into repeat dosing, and the 8 mg/kg cohort continued on 4 mg/kg. Patients were followed for 4 weeks after the last repeat dose.
Results: Thirty patients were randomised to study. Only mild to moderate adverse events were observed, mostly judged unrelated to study medication. There was one serious adverse event; flare of RA in a 0.15 mg/kg patient. The event was considered not related to HuMax-IL15. Standard laboratory safety parameters were unchanged and FACS analysis of leukocyte subsets were unremarkable. No patients raised antibodies against HuMax-IL15. In a pooled analysis of all dose cohorts, ACR20 response (from week 0) was achieved in 15 of 24 patients (63%), ACR50 in 38% and ACR70 in 25%. One patient never received repeat doses and was withdrawn from the analysis.
Conclusion: HuMax-IL15 at single doses up to 8 mg/kg and repeat doses up to 4 mg/kg is a safe, well-tolerated intervention in patients with active RA. Moreover, efficacy data suggest that IL-15 targeting may prove beneficial in active RA. |
