Label extension for canakinumab in Adult Onset Still’s Disease (AOSD) – Extrapolation from pediatrics to adults
Didier Renard (1), Bruno Bieth (1), Guido Junge (2), Antonio Speziale (2), Karine Lheritier (3)
(1) Pharmacometrics, Novartis, Basel, Switzerland (2) Development Franchise Immunology and Dermatology, Basel, Switzerland (3) Biostatistics, Novartis, Basel, Switzerland
Objectives: 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). Extensive literature review with biomarkers and gene expression profiling analyses showed superimposable systemic clinical features in systemic juvenile idiopathic arthritis (SJIA) and Adult Onset Still’s Disease (AOSD). They suggested that both clinical phenotypes represent a disease continuum ranging from pediatric (SJIA) to older, adult-onset (AOSD) patients [3]. Unfortunately, patients who experience onset of disease in adulthood, i.e. AOSD, cannot benefit from the canakinumab treatment option since it is only approved in the pediatric SJIA population. The objective of the PK/PD analysis was to extend the current label from SJIA to adult patients in the absence of adult data.
Methods: Population PK/PD modeling was performed on pooled canakinumab data across disease to evaluate the pharmacokinetics and exposure-response relationships by age groups to support extrapolation of the efficacy of canakinumab in SJIA to the adult population of AOSD patients.
Results: The distributions of canakinumab exposures predicted from a PK-IL1β model were overall comparable across age groups, including young adult SJIA patients and a simulated population of “SJIA-like” adult patients. Efficacy responses (DAS28 and CRP) to treatment with canakinumab, and corresponding exposure-response relationships, were comparable across age groups.
Conclusions: The population PK analyses and PKPD analyses supported the extrapolation of the efficacy and safety of canakinumab in SJIA to the adult population of AOSD patients. This main contribution helped in the EMA approval of extending the scope of SJIA indication of canakinumab to the treatment of AOSD disease.
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
[3] Martini A (2012) It is time to rethink juvenile idiopathic arthritis classification and nomenclature. Ann Rheum Dis 71(9): 1437-1439.
