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FRI0488 A Phase Iii Pivotal Umbrella Trial of Canakinumab in Patients with Autoinflammatory Periodic Fever Syndromes (Colchicine Resistant FMF, HIDS/MKD and TRAPS)
  1. F. De Benedetti1,
  2. J. Anton2,
  3. M. Gattorno3,
  4. H. Lachmann4,
  5. I. Kone-Paut5,
  6. S. Ozen6,
  7. J. Frenkel7,
  8. A. Simon8,
  9. A. Zeft9,
  10. E. Ben-Chetrit10,
  11. H. Hoffman11,
  12. Y. Joubert12,
  13. K. Lheritier12,
  14. A. Speziale12,
  15. G. Junge12
  1. 1IRCCS Ospedale Pediatrico Bambino Gesú, Rome, Italy
  2. 2Hospital Sant Joan de Déu, Barcelona, Spain
  3. 3Pediatric Rheumatology, G. Gaslini Institute, Genoa, Italy
  4. 4UK National Amyloidosis Centre, University College London Medical School, London, United Kingdom
  5. 5Hôpital Kremlin Bicetre, University of Paris SUD, Paris, France
  6. 6Hacettepe University Children's Hospital, Ankara, Turkey
  7. 7University Medical Center Utrecht, Utrecht
  8. 8Radboud University Medical Centre, Nijmegen, Netherlands
  9. 9Pediatrics Rheumatology, Cleveland Clinic, Cleveland, United States
  10. 10Rheumatology Unit, Hadassah–Hebrew University Medical Center, Jerusalem, Israel
  11. 11University of California, La Jolla, United States
  12. 12Novartis Pharma AG, Basel, Switzerland

Abstract

Background Periodic fever syndromes (PFS) are a group of rare auto-inflammatory conditions, which includes, among others, cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF-receptor associated periodic syndrome (TRAPS). Canakinumab (CAN), a fully human, highly specific anti-IL-1β neutralising monoclonal antibody, is effective in CAPS.1 IL-1β has been shown to be involved in the pathogenesis of FMF, HIDS/MKD and TRAPS, for whom no approved treatment exists. A series of small open label studies suggested efficacy of CAN in colchicine resistant/intolerant FMF (crFMF), HIDS/MKD and TRAPS.2,3 We report the efficacy and safety of CAN from the randomised treatment epoch of a phase III trial in patients (pts) with crFMF, HIDS/MKD or TRAPS.

Objectives Primary objective of this phase III pivotal trial was to demonstrate that CAN 150 mg (or 2 mg/kg for pts ≤40 kg) sc q4w is superior to placebo (PBO) in achieving a clinically meaningful response defined as resolution of the index flare at Day 15 and no new disease flares over 16 wks of treatment. Secondary objectives were: % pts who achieved a physician global assessment of disease activity (PGA) <2 (minimal/none); % pts with C-reactive protein (CRP) ≤10 mg/L; serum amyloid A level (SAA) ≤10 mg/L at Wk 16.

Methods The trial (NCT02059291) consists of 3 disease cohorts (crFMF, HIDS/MKD and TRAPS) and 4 study epochs (E1–4): a screening epoch (E1) of up to 12 wks, a randomised treatment epoch (E2) of 16 wks, a randomised withdrawal epoch (E3) of 24 wks and an open-label treatment epoch (E4) of 72 wks. Pts (age ≥2 years) with crFMF, HIDS/MKD or TRAPS with a flare during E1 were randomised (1:1) in E2 to receive CAN or PBO. Safety assessments included adverse events (AEs).

Results Of 181 pts (crFMF, n=63; HIDS/MKD, n=72; TRAPS, n=46) randomised in E2, 6 pts discontinued (5 PBO; 1 CAN). In all 3 disease cohorts, the proportion of pts who were responders for the primary outcome at Wk 16 was significantly higher with CAN vs PBO (Table). At Wk 16, a significantly higher proportion of pts achieved PGA score <2, CRP ≤10 mg/L and SAA ≤10 mg/L in the CAN group vs PBO in all 3 cohorts (Table). No new safety findings were reported in the CAN-treated pts through E2 (Table).

Conclusions These results demonstrated superior efficacy of canakinumab at dose level of 150 mg q4w after a 16 weeks treatment period compared to placebo. The overall safety profile was not distinct from previous controlled studies and expectations in an auto-inflammatory patient population.

Disclosure of Interest F. De Benedetti Grant/research support from: Pfizer, Abbvie, Roche, Novartis, Novimmune, BMS, J. Anton Grant/research support from: Novartis, Pfizer, Abbvie, Roche, SOBI, Consultant for: Novartis, M. Gattorno Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, Speakers bureau: Novartis, SOBI, H. Lachmann Consultant for: Novartis, SOBI, Takeda, GSK, Speakers bureau: Novartis, SOBI, I. Kone-Paut Grant/research support from: SOBI, Roche, Novartis, Consultant for: Novartis, SOBI, Pfizer, Abbvie, Chugai, S. Ozen Consultant for: Novartis, Speakers bureau: SOBI, J. Frenkel Grant/research support from: Novartis, SOBI, A. Simon Grant/research support from: CSL Behring, Novartis, Xoma/Servier, A. Zeft: None declared, E. Ben-Chetrit Consultant for: Novartis, H. Hoffman Grant/research support from: BMS, Consultant for: Novartis, SOBI, Regeneron, Speakers bureau: Novartis, Y. Joubert Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, A. Speziale Employee of: Novartis, G. Junge Employee of: Novartis

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