Efficacy and Safety of Canakinumab in Patients with Periodic Fever Syndromes (Colchicine-Resistant FMF, HIDS/MKD AND TRAPS): Results from a Phase 3, Pivotal, Umbrella Trial

Fabrizio De Benedetti¹, Jordi Anton², Eldad Ben-Chetrit³, Inmaculada Calvo⁴, Joost Frenkel⁵, Marco Gattorno⁶, Hal M. Hoffman⁷, Ozgur Kasapcopur⁸, Isabelle Koné-Paut⁹, Helen Lachmann¹⁰, Michel Moutschen¹¹, Seza Ozen¹², Pierre Quartier¹³, Anna Simon¹⁴, Andrew Zeft¹⁵, Karine Lheritier¹⁶, Antonio Speziale¹⁶ and Guido Junge¹⁶, ¹IRCCS Ospedale Pediatrico Bambino Gesú, Rome, Italy, ²Hospital Sant Joan de Déu, Barcelona, Spain, ³Rheumatology Unit, Hadassah—Hebrew University Medical Center, Jerusalem, Israel, ⁴Hospital Universitario y Piltecnico La Fe, Valencia, Spain, ⁵University Medical Center Utrecht, Utrecht, Netherlands, ⁶Pediatric Rheumatology, G. Gaslini Institute, Genoa, Italy, ⁷University of California at San Diego, San Diego, CA, ⁸Department of Pediatric Rheumatology, Istanbul University, Cerrahpasa Medical School, Department of Pediatric Rheumatology, Istanbul, Turkey, ⁹Hopital Kremlin Bicetre, University of Paris SUD, Paris, France, ¹⁰UK National Amyloidosis Centre, University College London Medical School, London, United Kingdom, ¹¹C.H.U. Sart-Tilman, Liege, Belgium, ¹²Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey, ¹³Hôpital Necker-Enfants Malades, Paris, France, ¹⁴General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ¹⁵Pediatrics Rheumatology, Cleveland Clinic, Cleveland, OH, ¹⁶Novartis Pharma AG, Basel, Switzerland

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Traps and canakinumab

Session Information

Date: Wednesday, November 16, 2016

Title: Pediatric Rheumatology – Clinical and Therapeutic Aspects III: Autoinflammatory Diseases and Juvenile Dermatomyositis

Session Type: ACR Concurrent Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose: Periodic fever syndromes (PFS) are rare auto-inflammatory conditions that include, among others, cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD), and TNF receptor-associated periodic syndrome (TRAPS).¹ Canakinumab (CAN), a fully human, highly specific anti-IL-1β neutralizing monoclonal antibody, is effective in CAPS.² IL-1β has been shown to be involved in the pathogenesis of FMF, HIDS/MKD and TRAPS, for which no or limited treatment options exist.¹Open-label studies have suggested the efficacy of CAN in colchicine-resistant/intolerant FMF (crFMF), HIDS/MKD, and TRAPS.^3-5 We report the efficacy and safety of CAN from the randomized treatment epoch of the Phase 3 pivotal study in patients (pts) with crFMF, HIDS/MKD or TRAPS.

Methods: The study (NCT02059291) consists of 3 disease cohorts (crFMF, HIDS/MKD and TRAPS) and 4 study epochs: a screening epoch (E1) of up to 12 wks, a randomized treatment epoch (E2) of 16 wks, a randomized withdrawal epoch (E3) of 24 wks and an open-label treatment epoch (E4) of 72 wks. Pts (aged ≥2 years) with a flare during E1 were randomized (1:1) in E2 to receive CAN or placebo (PBO). Primary objective was to demonstrate that CAN 150 mg (or 2 mg/kg for pts ≤40 kg) sc q4w is superior to PBO in achieving a clinically meaningful response, defined as resolution of the index flare at Day 15 and no new disease flares over 16 weeks (wks) of treatment. Safety assessments included adverse events (AEs) and serious AEs(SAEs).

Results: Of 181 pts (crFMF, n=63; HIDS/MKD, n=72; TRAPS, n=46) randomized in E2, 6 discontinued the study (5 PBO; 1 CAN). In all 3 disease cohorts, the proportion of 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 a PGA score <2, CRP ≤10 mg/L and SAA ≤10 mg/L in the CAN group vs PBO in all 3 cohorts. The most frequently affected system organ class across 3 cohorts was infections and infestations typically involving the upper respiratory tract. The incidence of SAEs was 8.6%, 4.7% and 11.8% in crFMF, TRAPS and HIDS/MKD cohorts,respectively.

Table

. Proportion of responders at Week 16 by cohort

Cohort

CAN (150 mg q4w), n/m (%)

Placebo n/m (%)

p value

crFMF

19/31 (61.3)

2/32 (6.3)

<0.001*

HIDS/MKD

13/37 (35.1)

2/35 (5.7)

0.0020*

TRAPS

10/22 (45.5)

2/24 (8.3)

0.0050*

*Statistical significance (1-sided) at the 0.025 level based on Fisher exact test/logistic regression model.

n=number of pts who responded; m=number of pts evaluated for response

Conclusion: These results demonstrated superior efficacy of canakinumab after a 16-week treatment period compared with placebo. The overall safety profile was not distinct from those reported in previous controlled studies. References: 1. Savic S and Wood P. Clin Med.2011;11(4):396–401. 2. Kuemmerle-Deschner JB, et al. Ann Rheum Dis. 2015;74:850. 3. Brik R, et al. Ann Rheum Dis. 2013;72:75. 4. Arostegui J, et al. Ann Rheum Dis. 2015;74:401. 5. Lachmann H, et al. Ann Rheum Dis. 2015;74:852.

Disclosure: F. De Benedetti, Pfizer, Abbvie, Roche, Novartis, Novimmune and BMS and SOBI, 2; J. Anton, Novartis Pharma AG, 2,Novartis Pharma AG, 5; E. Ben-Chetrit, Novartis Pharmaceutical Corporation, 5; I. Calvo, Pfizer, Abbvie, Novartis, Roche, 2,Gebro, Pfizer, Abbvie, Novartis, 8; J. Frenkel, Novartis and SOBI, 2; M. Gattorno, Novartis and SOBI, 2,Novartis and SOBI, 5; H. M. Hoffman, Novartis Pharmaceutical Corporation, 5,Novartis Pharmaceutical Corporation, 8; O. Kasapcopur, Novartis Pharmaceutical Corporation, 8; I. Koné-Paut, Novartis, SOBI and Roche, 2,Novartis, SOBI, Pfizer, Abbvie, Roche, 5; H. Lachmann, Novartis, SOBI, Takeda and GSK, 5,Novartis and SOBI, 8; M. Moutschen, None; S. Ozen, Novartis and SOBI, 8; P. Quartier, Abbvie, Chugai-Roche, Novartis, and Pfizer, 2,Abbvie, Novartis, Sobi and Roche, 5,Abbvie, Novartis, Pfizer, Roche and Sobi, 8; A. Simon, Novartis, Xoma/Servier, CSL Behring, 2,Novartis, Takeda, SOBI, Xoma, 5; A. Zeft, Merck, Opko Health, Arno therapeutics, 1,Novartis Pharmaceutical Corporation, 5; K. Lheritier, Novartis Pharma AG, 1,6Novartis Pharma AG, 3; A. Speziale, Novartis Pharma AG, 3; G. Junge, Novartis Pharma AG, 3.

To cite this abstract in AMA style:

De Benedetti F, Anton J, Ben-Chetrit E, Calvo I, Frenkel J, Gattorno M, Hoffman HM, Kasapcopur O, Koné-Paut I, Lachmann H, Moutschen M, Ozen S, Quartier P, Simon A, Zeft A, Lheritier K, Speziale A, Junge G. Efficacy and Safety of Canakinumab in Patients with Periodic Fever Syndromes (Colchicine-Resistant FMF, HIDS/MKD AND TRAPS): Results from a Phase 3, Pivotal, Umbrella Trial [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/efficacy-and-safety-of-canakinumab-in-patients-with-periodic-fever-syndromes-colchicine-resistant-fmf-hidsmkd-and-traps-results-from-a-phase-3-pivotal-umbrella-trial/. Accessed .

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