Efficacy and Safety of Canakinumab in Patients with Colchicine-Resistant Familial Mediterranean Fever, Hyper-Immunoglobulin D Syndrome/Mevalonate Kinase Deficiency and TNF Receptor-Associated Periodic Syndrome: 40 Week Results from the Pivotal Phase 3 Umbrella Cluster Trial

Fabrizio De Benedetti¹, Joost Frenkel², Inmaculada Calvo³, Marco Gattorno⁴, Michel Moutschen⁵, Pierre Quartier⁶, Ozgur Kasapcopur⁷, Seza Ozen⁸, Jordi Anton⁹, Isabelle Koné-Paut¹⁰, Helen Lachmann¹¹, Hal M. Hoffman¹², Eldad Ben-Chetrit¹³, Anna Shcherbina¹⁴, Michaël Hofer¹⁵, Philip J Hashkes¹⁶, Andrew Zeft¹⁷, Karine Lheritier¹⁸, Yankun Gong¹⁹, Antonio Speziale¹⁸ and Guido Junge¹⁸, ¹Division of Rheumatology, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy, ²University Medical Center Utrecht, Utrecht, Netherlands, ³Pediatric Rheumatology, Hospital Universitario i Politecnic La Fe, Valencia, Spain, ⁴Pediatric Rheumatology, G. Gaslini Institute, Genoa, Italy, ⁵C.H.U. Sart-Tilman, Liege, Belgium, ⁶Necker-Enfants Malades Hospital, Paris, France, ⁷Department of Pediatric Rheumatology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey, ⁸Department of Pediatrics, Division of Rheumatology, Hacettepe University Children's Hospital, Ankara, Turkey, ⁹Hospital Sant Joan de Déu, Barcelona, Spain, ¹⁰Department of Paediatric Rheumatology, Hôpital Kremlin Bicetre, University of Paris SUD, Paris, France, ¹¹UK National Amyloidosis Centre, University College London Medical School, London, United Kingdom, ¹²University of California, San Diego, La Jolla, CA, ¹³Rheumatology Unit, Hadassah—Hebrew University Medical Center, Jerusalem, Israel, ¹⁴Immunology, Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation, ¹⁵Unité romande d’immuno-rhumatologie pédiatrique, CHUV, University of Lausanne, Lausanne, Switzerland, ¹⁶Pediatrics Rheumatology; Shaare-Zedek Medical Center, Jerusalem, Israel, ¹⁷Pediatrics Rheumatology, Cleveland Clinic, Cleveland, OH, ¹⁸Novartis Pharma AG, Basel, Switzerland, ¹⁹Beijing Novartis Pharma Co. Ltd., Beijing, China

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: October 19, 2016

Keywords: canakinumab and familial Mediterranean fever, Late-Breaking 2016

Session Information

Date: Tuesday, November 15, 2016

Title: ACR Late-Breaking Poster Session

Session Type: ACR Late-breaking Abstract Session

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

Background/Purpose: Evidence points to the role of abnormal IL-1β production in familial Mediterranean fever (FMF), hyper-immunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD) and TNF receptor-associated periodic syndrome (TRAPS). Analysis of the efficacy of canakinumab (CAN), a fully human anti-IL-1β monoclonal antibody, in the double blind randomized epoch 2 of the phase 3 CLUSTER trial in patients (pts) with colchicine-resistant FMF (crFMF), HIDS/MKD or TRAPS has demonstrated highly significant differences vs placebo (PBO) in the primary outcome (resolution of the index flare by Day 15 and no subsequent flares up to week [wk] 16) in the 3 diseases¹. Here we report the results from the subsequent epoch 3 (up to wk 40) that included a randomized withdrawal phase to evaluate CAN at a prolonged dosing interval (8 wks [q8w]) or complete discontinuation.

Methods: The study comprises 3 disease cohorts (crFMF, HIDS/MKD and TRAPS) and 4 epochs: a 12-wk screening epoch (E1), a 16-wk randomized treatment epoch (E2), a 24-wk randomized withdrawal epoch (E3) and a 72-wk open-label treatment epoch (E4). Pts who were initially randomized to CAN 150 mg every 4 wks (q4w) and did not flare in E2 were re-randomized 1:1 to CAN 150 mg q8w or PBO in E3. The endpoint of E3 was the proportion of pts who maintained control of disease (no flares: PGA ≤2 and CRP ≤30 mg/L) between Wk 16 and Wk 40 after re-randomization to CAN 150 mg q8w vs PBO. Moreover, in order to gain additional information on the maintenance dose in the long-term, pts who escaped to open-label CAN during E2, were dosed to open-label CAN 150mg q8w during E3. Pts with a flare could be escalated up to 300 mg q4w.

Results: 42 pts who were CAN (150 mg q4w) responders in E2 were re-randomized to CAN 150 mg q8w or PBO in E3. At Wk 40, the proportion of responders was numerically higher in the CAN vs PBO group in all 3 disease cohorts (Table). Overall in E3, including pts treated in open-label, 49% of the crFMF pts, 53% of the TRAPS pts and 23% of the HIDS/MKD pts maintained disease control with a prolonged dosing interval (150 mg q8w). Up-titration to 300 mg q4w was needed in few pts with crFMF (10%) or TRAPS (8%) and in 29% of those with HIDS/MKD. No new safety findings were reported in CAN-treated pts through E3, with no toxicity accumulation (Table). No deaths were reported in the 3 disease cohorts.

Conclusion: The results of E3 in this pivotal trial confirm long-term efficacy of CAN in crFMF, HIDS/MKD and TRAPS, and yield information on the long-term dose needed to control disease, with approximately half of the pts with crFMF or TRAPS and approximately 1/3 of the pts with HIDS/MKD showing no flare at a prolonged dose interval administration of 150 mg q8w. The higher dose of 300 mg q4w was needed in few pts with crFMF or TRAPS and in 1/3 of the pts with HIDS/MKD. No new safety issues were reported over 40 wks of CAN treatment; the safety profile was not distinct from previous controlled studies.

De Benedetti F, et al. Ann Rheum Dis 2016;75(Suppl2):615.

Disclosure: F. De Benedetti, Novartis, Pfizer, Abbvie, Roche, Novimmune, BMS, 2; J. Frenkel, Novartis, SOBI, 2; I. Calvo, Pfizer, Abbvie, Novartis, Roche, 2,Gebro, Pfizer, Abbvie, Novartis, 8; M. Gattorno, Novartis, SOBI, 2,Novartis, SOBI, 5,Novartis, SOBI, 8; M. Moutschen, None; P. Quartier, Abbvie, Chugai-Roche, Novartis, Pfizer, 2,Abbvie, Novartis, Sobi, Roche, 5,Abbvie, Novartis, Pfizer, Roche, Sobi, 8,Sanofi-Aventis Pharmaceutical, 9,Novimmune, 9; O. Kasapcopur, Novartis Pharmaceutical Corporation, 5,Novartis Pharmaceutical Corporation, Pfizer, 8; S. Ozen, Novartis, SOBI, 8; J. Anton, Novartis Pharmaceutical Corporation, 2,Novartis Pharmaceutical Corporation, 5; I. Koné-Paut, SOBI, Novartis, Roche, 2,Novartis, SOBI, Pfizer, Abbvie, Roche/Chugai, 5; H. Lachmann, Novartis, SOBI, Takeda, GSK, 5,Novartis, SOBI, 8; H. M. Hoffman, Novartis Pharmaceutical Corporation, 5,Novartis Pharmaceutical Corporation, 8; E. Ben-Chetrit, Novartis Pharmaceutical Corporation, 5; A. Shcherbina, None; M. Hofer, Novartis Pharmaceutical Corporation, 5; P. J. Hashkes, Novartis Pharmaceutical Corporation, 2,Novartis Pharmaceutical Corporation, 5,Novartis Pharmaceutical Corporation, 8; A. Zeft, Merck, Opko Health, Arno therapeutics, 1,Novartis Pharmaceutical Corporation, 5; K. Lheritier, Novartis Pharma AG, 1,Novartis Pharma AG, 3; Y. Gong, Novartis Pharmaceutical Corporation, 3; A. Speziale, Novartis Pharma AG, 3; G. Junge, Novartis Pharmaceutical Corporation, 3.

To cite this abstract in AMA style:

De Benedetti F, Frenkel J, Calvo I, Gattorno M, Moutschen M, Quartier P, Kasapcopur O, Ozen S, Anton J, Koné-Paut I, Lachmann H, Hoffman HM, Ben-Chetrit E, Shcherbina A, Hofer M, Hashkes PJ, Zeft A, Lheritier K, Gong Y, Speziale A, Junge G. Efficacy and Safety of Canakinumab in Patients with Colchicine-Resistant Familial Mediterranean Fever, Hyper-Immunoglobulin D Syndrome/Mevalonate Kinase Deficiency and TNF Receptor-Associated Periodic Syndrome: 40 Week Results from the Pivotal Phase 3 Umbrella Cluster Trial [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/efficacy-and-safety-of-canakinumab-in-patients-with-colchicine-resistant-familial-mediterranean-fever-hyper-immunoglobulin-d-syndromemevalonate-kinase-deficiency-and-tnf-receptor-associated-periodic/. Accessed .

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