Use of population PK/PD modeling to support the regulatory approval of canakinumab as first biologic treatment in patients with periodic fever syndromes
Bruno Bieth (1), Guido Junge (2), Antonio Speziale (2), Shephard Mpofu (2), Karine Lheritier (3), Yankun Gong (4), Andrijana Radivojevic (5), Didier Renard (1)
(1) Pharmacometrics, Novartis, Basel, Switzerland (2) Development Franchise Immunology and Dermatology, Basel, Switzerland (3) Biostatistics, Novartis, Basel, Switzerland (4) Biostatistics, Novartis Pharmaceuticals AG, Shanghai, China (5) Pharmacometrics, Novartis Pharmaceuticals AG, East-Hanover, USA
Objectives: Periodic Fever Syndromes is a group of rare orphan diseases classified together under a single term and classically consists of 4 separate conditions: Cryopyrin Associated Periodic Syndrome (CAPS), colchicine resistant Familial Mediterranean Fever (crFMF), Hyper-immunoglobulin D (hyper-IgD) Syndrome/ Mevalonate Kinase Deficiency (HIDS/MKD) and TNF receptor Associated Periodic Syndrome (TRAPS).
Canakinumab (ACZ885) is a high-affinity fully human monoclonal anti-human interleukin-1β (IL-1β) antibody. IL-1β is recognized as one of the principal proinflammatory cytokines, in a variety of inflammatory conditions [1], [2]. As a potent neutralizer of IL-1β, it is expected to treat the underlying structural features of arthritis (inflammation, bone and cartilage degradation). Canakinumab was previously approved in CAPS, and had been shown to be effective in isolated case reports and preliminary studies regarding the other Periodic Fevers Syndromes.
The objective of the PK/PD analysis was to support the recommended dosing regimen in the 3 remaining PFS conditions.
Methods: PK and efficacy/safety data were obtained from a phase III double-blind, placebo controlled umbrella study in PFS patients with subcutaneous administration of canakinumab every 4 weeks (up-titration in case of lack or incomplete response to the initial dosing regimen). PK data from another proof-of-concept study and from other phase III studies in CAPS were also included.
Population PK/PD modeling including one-compartment PK model and PK/PD model for the probability of flare (primary efficacy endpoint) were developed to explore the exposure response relationship for selected efficacy and safety outcomes.
Results: The pharmacokinetics of canakinumab in PFS was consistent with other indications (e.g. CAPS). The treatment was associated with decreased levels of acute phase proteins (CRP and SAA) and improved Physician Global Assessment, which are key components of flare (primary efficacy endpoint). The exposure-response modeling for the probability of flare suggested a difference in drug sensitivity across disease conditions. HIDS/MKD and TRAPS patients tended to have higher IL-1β levels and require higher doses to prevent flares.
Conclusions: The population PK knowledge from previous indications could be leveraged in the new PFS disease conditions. Analyses supported the up-titration dosing scheme in case of new flare, especially in patients with HIDS/MKD and TRAPS. This work supported the simultaneous approval of canakinumab in 3 PFS conditions.
References:
[1] Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood; 87(6):2095-147.
[2] Dinarello CA (2005) Blocking IL-1 in systemic inflammation. J Exp Med; 201(9):1355-9.