Pharmacokinetic and Pharmacodynamic Characteristics of Canakinumab in Patients with Periodic Fever Syndromes: Results from a Phase III Pivotal Umbrella Trial

Joost Frenkel¹, Jordi Anton², Avi Livneh³, Eldad Ben-Chetrit⁴, Paul Brogan⁵, Segundo Bujan-Rivas⁶, Tamás Constantin⁷, Fabrizio De Benedetti⁸, Marco Gattorno⁹, Ahmet Gül¹⁰, Hal M. Hoffman¹¹, Isabelle Kone-Paut¹², Helen Lachmann¹³, Seza Ozen¹⁴, Anna Simon¹⁵, Jeroen Van der Hilst¹⁶, Andrew Zeft¹⁷, Antonio Speziale¹⁸, Guido Junge¹⁸ and Lucy Xu¹⁹, ¹University Medical Center,Utrecht, Utrecht, Netherlands, ²Hospital Sant Joan de Déu, Barcelona, Barcelona, Spain, ³Department of Medicine F, Sheba Medical Center, Tel Hashomer, Israel, ⁴Medicine A Rheum Unit, Hadassah University Hosp, Jerusalem, Israel, ⁵Department of Paediatric Rheumatology, UCL Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom, ⁶Vall d'Hebron Hospital, Barcelona, Barcelona, Spain, ⁷Unit of Paediatric Rheumatology, 2nd Dpt of Pediatrics, Semmelweis University, Budapest, Hungary, ⁸Division of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Roma, Italy, Rome, Italy, ⁹UO Pediatria 2, Istituto Giannina Gaslini, Genova, Italy, ¹⁰Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey, ¹¹Pediatric Allergy, Immunology and Rheumatology, University of California at San Diego/Rady Children Hospital, La Jolla, CA, ¹²PRINTO, Genoa, Italy, ¹³UK National Amyloidosis Centre, University College London Medical School, London, United Kingdom, ¹⁴Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara, Turkey, ¹⁵National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ¹⁶Department of infectious disease and immunity, Jessa Hospital, Hasselt, Hasselt, Belgium, ¹⁷Pediatric Rheumatology, The Cleveland Clinic, Cleveland, OH, ¹⁸Novartis Pharma AG, Basel, Switzerland, ¹⁹Novartis Pharmaceuticals Corporation, East Hanover, NJ

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: canakinumab

Session Information

Date: Tuesday, November 15, 2016

Title: Pediatric Rheumatology – Clinical and Therapeutic Aspects - Poster III: Systemic JIA, Autoinflammatory Syndromes, Scleroderma, Vasculitis, Miscellaneous

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: The pharmacokinetics (PK) of canakinumab (CAN) and total interleukin (IL)-1β kinetics have been well investigated in CAPS patients (pts).¹ Here we present the PK and pharmacodynamics (PD) of CAN (solution for injection-liquid in vial [LIVI]) from the randomized treatment epoch (primary analysis up to Week 16) of a Phase III study (NCT02059291) in colchicine-resistant/intolerant familial Mediterranean fever (crFMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD), and TNF receptor associated periodic syndrome (TRAPS) pts.

Methods: The study comprised 3 disease cohorts (crFMF, HIDS/MKD, and TRAPS). Each cohort followed the same study design across 4 epochs (screening epoch [up to 12 weeks], randomized treatment epoch [16 weeks], randomized withdrawal epoch [24 weeks] and open-label treatment epoch [72 weeks]). Pts (age, ≥2 years) with crFMF, HIDS/MKD, or TRAPS who had a flare during Epoch 1 were randomized (1:1) in Epoch 2 to receive subcutaneous (sc) CAN 150 mg (or 2 mg/kg for pts weighing ≤40 kg) every 4 weeks (q4w) or placebo. Blinded uptitration (up to 300 mg) was allowed for pts not resolving the index flare by Day 15. Serum samples for CAN concentrations and total IL-1β were collected at baseline (Day 1), and trough samples, at weeks 2, 4, 8, 12, and 16.

Results: In crFMF, HIDS/MKD, and TRAPS pts, the serum clearance and steady-state volume of distribution of CAN varied according to body weight, and were estimated to be 0.14±0.04 L/day and 4.96±1.35 L, respectively. The estimated half-life of CAN was 25.6±6.4 days. CAN minimal concentration at Week 16 following 150 mg sc q4w dosing was estimated to be 15.3±6.6 μg/mL. The estimated steady-state area under the serum concentration-time curve from time zero to the end of the dosing interval tau (AUC_tau) was 648±202 μg.day/mL. Similar results were obtained in all 3 diseases. CAN binding to circulating IL-1β was demonstrated by increase in total IL-1β following CAN dosing in all 3 diseases. In pts requiring uptitration to 300 mg, levels of total IL-1β were higher, suggesting higher production of IL-1β, and therefore the need for a higher dose.

Conclusion: This was the first study to evaluate the PK of canakinumab given in the LIVI form. The results observed in crFMF, HIDS/MKD, and TRAPS pts were similar to those observed in other indications (CAPS and SJIA) using the lyophilisate form. These data suggested that the new formulation did not affect the PK/PD of canakinumab and similar to CAPS, patients with higher levels of IL-1β require canakinumab uptitration to achieve optimal disease control. Reference: 1.Chakraborty A, et al. Clin Pharmacokinet. 2012;51:e1–18.

Disclosure: J. Frenkel, Novartis Pharmaceutical Corporation and SOBI, 2; J. Anton, Novartis Pharmaceutical Corporation, Pfizer, Abbvie, Roche, SOBI, 2; A. Livneh, None; E. Ben-Chetrit, Novartis Pharmaceutical Corporation, 5; P. Brogan, Roche Pharmaceuticals, SOBI, 5; S. Bujan-Rivas, None; T. Constantin, None; F. De Benedetti, Novartis Pharmaceutical Corporation, Pfizer, Abbvie, Roche, Novimmune, BMS, 2; M. Gattorno, Novartis, SOBI, 2,Novartis, SOBI, 5,Novartis, SOBI, 8; A. Gül, None; H. M. Hoffman, BMS, 2,Novartis Pharmaceutical Corporation, SOBI, Regeneron, 5,Novartis Pharmaceutical Corporation, 8; I. Kone-Paut, Novartis Pharmaceutical Corporation, SOBI, Roche, 2,Novartis Pharmaceutical Corporation SOBI, Pfizer, Abbvie, Chugai, 5; H. Lachmann, Novartis Pharmaceutical Corporation, SOBI, Takeda, GSK, 5,Novartis Pharmaceutical Corporation, SOBI, 8; S. Ozen, None; A. Simon, Novartis Pharmaceutical Corporation, CSL Behring, Xoma/Servier, 2; J. Van der Hilst, None; A. Zeft, Merck, OPKO, ARNI, 1; A. Speziale, Novartis Pharmaceutical Corporation, 3; G. Junge, Novartis Pharmaceutical Corporation, 3; L. Xu, Novartis Pharmaceutical Corporation, 3.

To cite this abstract in AMA style:

Frenkel J, Anton J, Livneh A, Ben-Chetrit E, Brogan P, Bujan-Rivas S, Constantin T, De Benedetti F, Gattorno M, Gül A, Hoffman HM, Kone-Paut I, Lachmann H, Ozen S, Simon A, Van der Hilst J, Zeft A, Speziale A, Junge G, Xu L. Pharmacokinetic and Pharmacodynamic Characteristics of Canakinumab in Patients with Periodic Fever Syndromes: Results from a Phase III Pivotal Umbrella Trial [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/pharmacokinetic-and-pharmacodynamic-characteristics-of-canakinumab-in-patients-with-periodic-fever-syndromes-results-from-a-phase-iii-pivotal-umbrella-trial/. Accessed .

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