[2008] [OP-0006] TREATMENT OF CRYOPYRIN ASSOCIATED PERIODIC FEVER SYNDROME WITH A LONG-ACTING FULLY HUMAN ANTI-IL-1BETA MONOCLONAL ANTIBODY (ACZ885)
H.J. Lachmann1, P. Lowe2, M. Offer1, C. Rordorf2, X. Gitton3, N.P. Patel3, P.N. Hawkins1 1National Amyloidosis Centre, Department of Medicine, Royal Free and University College Medical School, Royal Free Hospital, London, United Kingdom; 2Translational Medicine and Modelling and Simulation; 3Clinical Development, Novartis Pharma AG, Basel, Switzerland
Background: ACZ885, a fully human anti-IL-1β monoclonal antibody, was studied for the treatment of CAPS – a rare autoinflammatory disorder caused by mutations in NLRP3. Mathematical modelling and simulation was used to propose a dose and regimen (posology) of ACZ885 for a Phase III confirmatory clinical study.
Objectives: The primary objective was to use modeling and simulation to design a confirmatory Phase III study based on data from an open-label study with CAPS patients receiving ACZ885 individualised treatment.
Methods: The pharmacokinetics of ACZ885 was described well by a two compartment model. The probability of occurrence of inflammatory relapse, due to over expression of IL-1β was thus inversely related to the drug concentration. Based on model simulations, a 48-week, three-part, multicentre, Phase III study was designed.
Results: The phase III study design was built on a model based on data from 4 patients, which were observed for up to 1.5 years receiving individualised re-dosing upon relapse. The patients were studied for 16 cycles in total (2 pts 4.5, 2 pts 3.5 cycles) and individual PK/PD measurements were taken. The drug was well tolerated and resulted in improvement of clinical symptoms within 1 day and a complete clinical remission within 7 days. Duration of clinical remission varied with dose and had an interquartile range of 68-202 days. PK profiles were modeled for the simulation. The model fitted the PK and clinical remission data very well, with ACZ885 having a plasma half life of 29 days and a critical drug concentration of 1.1 mcg/mL where there was a 50:50 probability of clinical relapse. Simulations from the model predicted that regular dosing of 150 mg every 8 weeks should maintain drug concentrations, provide a low probability of relapse, and hence produce sustained disease control in patients over 40 kg. Using the modeling a confirmatory Phase III study was designed which includes an 8-week, open-label, treatment period to identify ACZ885 responders (part 1; 1 single injection of ACZ885); a 24-week, randomised, double-blind, placebo-controlled period to compare the efficacy of ACZ885 with placebo (part 2, treatment every 8 weeks), and a 16-week, open-label, active treatment period (part 3). Complete responders without disease flare by Week 8 are randomised (1:1) to ACZ885 or placebo in part 2. More than 30 patients have been enrolled and randomised to part II of the study.
Conclusion: ACZ885, a new IL-1β inhibitor, provides long lasting remission in CAPS patients after one administration. PK-clinical response modelling suggested that ACZ885 150 mg sc every 8 weeks should maintain disease control. The model hypothesis is being tested in an ongoing confirmatory Phase III study.
Ann Rheum Dis 2008;67(Suppl II):49
Inflammasome and cytokine
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