[2008] [OP-0178] LONG LASTING RESPONSE TO ACZ885 IN PATIENTS WITH MUCKLE-WELLS-SYNDROME (MWS)
J.B. Kümmerle-Deschner1, N. Tzaribachev1, S. Hansmann1, K. Gramlich1, S.D. Felix2, M. Diaz-Lorente3, M. Gantenbein3, A. Giesen3, C. Rordorf2 1Division of Pediatric Rheumatology, University Hospital Tuebingen, Tuebingen, Germany; 2Exploratory Clinical Development, Novartis Pharma AG, Basel, Switzerland; 3Clinical Development and Medical Affairs, Novartis Pharma GmbH, Nuernberg, Germany
Background: MWS is a rare auto-inflammatory disease caused by mutations in the CIAS 1 gene and likely driven by excessive activity of Interleukin-1β (IL-1β). Clinical features are skin rashes, arthralgia, fever, progressive sensorineural hearing loss and possible development of amyloidosis. Treatment with anakinra, a soluble IL-1 receptor antagonist, has been shown to be safe and effective [1]; however, frequent and high dose injections are not tolerated well by patients. ACZ885 is a new long-acting human IgG1 anti-IL-1β monoclonal antibody. Herein, we report a single-centre interim analysis of an open label phase II study to investigate the safety and efficacy of ACZ885.
Methods: Patients were eligible for the study if they had documented molecular diagnosis of CIAS 1 mutation and active disease requiring medical intervention. Patients received a single s.c. injection of ACZ885 (adults 150 mg/children 2 mg/kg), followed by an observation period and re-dosing upon relapse. Complete response was defined by physician's global assessment of disease activity and assessment of skin disease as ≤ 2 on a 5-point scale (1=absent, 2=minimal, 3=mild, 4=moderate, 5=severe), respectively and normal serum values (< 10 mg/L) of C-reactive protein (CRP) and/or serum amyloid A (SAA). In case of incomplete response within 7 days ACZ885 5 mg/kg was added by i.v. application.
Results: 12 patients (7 female, 5 male) were enrolled, median age 27, 6 (4, 3–47, 4) (4 children below 14 years); 9 patients had a medical history of treatment with anakinra up to 8 mg/kg. All 12 patients treated with ACZ885 achieved a complete and rapid clinical and serological response (table). Two children and one adult received i.v. applications. Median time to re-dosing was 92 days (9 patients) after the first and 66 days (6 patients) after the second treatment cycle. Two patients remained relapse free for 106 days. ACZ885 was well tolerated. AEs were upper respiratory tract infections (7) and elevated pancreas amylase and lipase (2). One patient experienced a SAE (vertigo).
| Parameters < | | Baseline | Day 8 | Day 38 | Day 68 | Day 98 |
|---|
| | n=12 | n=12 | n=12 | n=9 | n=3 |
|---|
| | before ACZ885 | following 1st ACZ885 dose |
|---|
| Physician's assessment | DA (1-5) | 4 | 1 | 1 | 3 | 4 | | Patient's assessment | PD (0-4) | 2 | 0 | 0,5 | 1 | 2 | | ESR (mm/h) | | 24 | 11 | 8 | 8 | 26 | | CRP (mg/L) | | 10,9 | 1,15 | 0,6 | 0,8 | 4,4 | | SAA (mg/L) | | 16,05 | 1,5 | 1,75 | 2,9 | 17 |
All numbers are median values; DA, disease activity, PD, patient diary (0-4 scale).
Conclusion: ACZ885 achieved a complete and long lasting response in 12 MWS patients. Long treatment-free intervals of up to 106 days are a great advantage in patients who tolerate daily injections poorly. The first predictor of disease progression was clinical deterioration (physician's global assessment), while the rise in inflammatory markers was observed at a later timepoint.
References: 1. Hawkins PN et al. N Engl J Med 2003;348:2583-4
Ann Rheum Dis 2008;67(Suppl II):104
Abstract Session: Periodic fever syndromes; take two Aspirin, but you still call me in the morning ...
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