M Gattorno

Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): an open-label, phase II study.

Objective To evaluate the efficacy of canakinumab, a high-affinity human monoclonal anti-interleukin-1β antibody, in inducing complete or almost complete responses in patients with active tumour necrosis factor receptor-associated periodic syndrome (TRAPS). Methods Twenty patients (aged 7–78u2005years) with active recurrent or chronic TRAPS were treated with canakinumab 150u2005mg every 4u2005weeks for 4u2005months (2u2005mg/kg for those ≤40u2005kg) in this open-label, proof-of-concept, phase II study. Canakinumab was then withdrawn for up to 5u2005months, with reintroduction on relapse, and 4 weekly administration (subsequently increased to every 8u2005weeks) for 24u2005months. The primary efficacy variable was the proportion of patients achieving complete or almost complete response at day 15, defined as clinical remission (Physicians Global Assessment score ≤1) and full or partial serological remission. Results Nineteen patients (19/20, 95%; 95% CI 75.1% to 99.9%) achieved the primary efficacy variable. Responses to canakinumab occurred rapidly; median time to clinical remission 4u2005days (95% CI 3 to 8u2005days). All patients relapsed after canakinumab was withdrawn; median time to relapse 91.5u2005days (95% CI 65 to 117u2005days). On reintroduction of canakinumab, clinical and serological responses were similar to those seen during the first phase, and were sustained throughout treatment. Canakinumab was well tolerated and clinical responses were accompanied by rapid and sustained improvement in health-related quality of life. Weight normalised pharmacokinetics of canakinumab, although limited, appeared to be consistent with historical canakinumab data. Conclusions Canakinumab induces rapid disease control in patients with active TRAPS, and clinical benefits are sustained during long-term treatment. Trial registration number NCT01242813; Results.

FRI0488 A Phase Iii Pivotal Umbrella Trial of Canakinumab in Patients with Autoinflammatory Periodic Fever Syndromes (Colchicine Resistant FMF, HIDS/MKD and TRAPS)

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

THU0396 Efficacy and safety of canakinumab in patients with TNF receptor associated periodic syndrome (TRAPS)

Background TNF-receptor associated periodic syndrome (TRAPS) is a rare dominantly inherited periodic fever syndrome involving a genetic mutation of the TNF Super Family Receptor 1A gene. Usually presenting in childhood, it is characterized by recurrent fever attacks associated with rash, musculoskeletal and abdominal pain, conjunctivitis, and periorbital edema and ∼10% develop renal AA amyloidosis. Case reports suggest successful treatment with the IL-1 receptor antagonist anakinra. Canakinumab is a fully human monoclonal selective anti-IL-1β antibody with a half-life of ∼4 wks. Here we report 4-month interim data of canakinumab treatment in patients with active TRAPS. Objectives To assess the efficacy and safety of canakinumab patients with active TRAPS. Methods Twenty pts with a median age of 18 years (7 to 78 yrs) and active TRAPS entered a 3-part trial comprising of 4 months of open-label 150mg (or 300mg) sc canakinumab injection every 4 weeks followed by 5 months follow-up (treatment withdrawal), and then 24 months open-label treatment. Pts were evaluated clinically by a 5-point physician’s global assessment (PGA) disease activity scale and serologically by CRP and SAA levels. The primary endpoint was complete or almost complete response at Day 15. Complete response was defined as clinical remission (PGA of 0 or 1 [absent or minimal]) and normal CRP and/or SAA. Almost complete response was clinical remission and elevated but ≥70% reduction of baseline CRP and/or SAA. Those who without response by Day 8 were eligible to receive another 150mg sc injection that day and remain at the 300mg dose thereafter. Results On Day 8, 16 (80%) achieved complete/almost complete response and 18 (90%) achieved clinical remission.The 2 pts without clinical remission were dose up-titrated to 300mg. The primary endpoint was met. At Day 15, 19/20 (95%) achieved complete/almost complete response, including all 4 who did not achieve it at Day 8. Clinical remission was maintained for all from Day 15 onwards in the 4-month treatment period except for 1 patient with a relapse at Day 85 that responded to the scheduled canakinumab dose. Median time to clinical remission was 4 days (95% CI:3,8). Median baseline CRP (125 mg/L) and SAA (207 mg/mL) normalized to 4mg/L from Day 15 onwards. 95% of patients reported at least 1 adverse event (AE). Infection, mostly upper respiratory tract infections (URI), was the most common (n=13, 65%) category of AE reported. One serious AE, a URI, was reported. All patients continued into the 5 months follow-up and entered the 24-month final open-label treatment period. Conclusions In this on-going study, canakinumab produced a rapid and highly effective clinical and serological benefit which was maintained with monthly dosing in patients with TRAPS. Canakinumab demonstrated an acceptable safety and tolerability profile in this small study. Data confirm that IL-1β plays a pivotal role in TRAPS and further study is needed to better define canakinumab treatment. Disclosure of Interest M. Gattorno Grant/Research support from: Novartis, Consultant for: Novartis, Speakers Bureau: Novartis, L. Obici Consultant for: Novartis, A. Meini Consultant for: Novartis, V. Tormey: None Declared, K. Abrams Shareholder of: Novartis, Employee of: Novartis, N. Davis Employee of: Novartis, C. Andrews Shareholder of: Novartis, Employee of: Novartis, H. Lachmann Consultant for: Novartis

Rapid and sustained effect of anti-TNF treatment in patients with ADA2 deficiency.

Mutations of CERC1 have been recently reported as causative of an inflammatory condition characterized by polyarteritis, cerebral stroke and immunodeficiency; the response to immunosuppressors and biological drugs is not univocal.

The phenotypic variability of PAPA syndrome: evidence from the Eurofever Registry

8th International Congress of Familial Mediterranean Fever and Systemic Autoinflammatory Diseases

OR10-006 - Canakinumab in patients with TRAPS

TNF-receptor associated periodic syndrome (TRAPS) is a rare, dominantly inherited periodic fever syndrome due to mutations of the TNFRSF1A gene. The IL-1 receptor antagonist anakinra has been reported to be an efficacious daily treatment. Canakinumab (CAN) is a fully human monoclonal selective anti-IL-1β antibody with a T1/2 of ~4 wks. Interim clinical and PK data of CAN treatment in patients with active TRAPS are presented.

PReS-FINAL-2335: Preliminary analysis of 85 patients with mevalonate kinase deficiency from the eurofever registry

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease, caused by mutations in the isoprenoid pathway that lead to fever episodes. Approximately 300 MKD patients are known.

FRI0489 Canakinumab Improves Patient Reported Outcomes in Patients with Periodic Fever Syndromes

Background Periodic Fever Syndromes (PFS) are rare autoinflammatory conditions including Familial Mediterranean Fever (FMF), Hyper-IgD Syndrome/ Mevalonate Kinase Deficiency (HIDS/MKD), and TNF-Receptor Associated Periodic Syndrome (TRAPS).1 It has been shown that colchicine-resistant FMF (crFMF), HIDS/MKD and TRAPS considerably impact physical and emotional aspects of patients lives.2–4 Open label studies suggested that canakinumab (CAN), a fully human and highly specific anti-IL-1β monoclonal antibody, is efficacious in crFMF, HIDS/MKD and TRAPS.5–7 To date, there is no data showing the effect of CAN on Health-Related Quality of Life (HRQoL) in PFS patients. Objectives To evaluate the effect of CAN on HRQoL using Child Health Questionnaire – Parent Form 50 (CHQ-PF50) and SF-12 Health Survey (SF-12) in PFS patients. Methods In a Phase 3 randomised placebo controlled study of CAN in PFS (NCT02059291), SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS) were assessed in adults. For children (>5–<18 years), CHQ-PF50 Physical (PhS) and Psychosocial (PsS) Summary scores were assessed. Results 181 patients were randomised to CAN or placebo in 3 cohorts (63 crFMF, 72 MKD/HIDS, 46 TRAPS). 71 adults ≥18 years and 110 children (age range ≥2–<18 years). Patients reported early clinically meaningful improvement in SF-12 PCS scores reported at Week (Wk) 5 which were sustained and increased to a large effect size by Wk 16 for all indications (Table). Similarly, clinically meaningful improvements in SF-12 MCS, CHQ-PF50 PhS and PsS was observed in all indications, with the exception of PsS in HIDS/MKD and TRAPS patients (Table).Table 1. Patient reported outcomes Mean change from baseline (n/N) crFMF HIDS/MKD TRAPS Week 5 Week 16 Week 5 Week 16 Week 5 Week 16 SF-12 PCS 7.9 (29/30) 9.55 (30/31) 13.81 (15/15) 13.81 (14/14) 9.63 (16/17) 11.64 (13/14) SF-12 MCS 4.83 (29/30) 4.27 (30/31) 6.41 (15/15) 8.14 (14/14) 5.65 (16/17) 5.51 (13/14) CHQ-PF50 PhS 13.2 (21/24) 20.1 (18/21) 5.5 (32/34) 9.9 (27/29) 7.4 (16/18) 14.9 (13/14) CHQ-PF50 PsS 4.1 (21/24) 7.2 (18/21) 1.8* (32/34) 5.2 (27/29) 0.9* (16/18) 1.2* (13/14) N = total number of patients; n = patients who received at least one dose of canakinumab. *Minimal important difference8,9from baseline was not achieved. Conclusions Canakinumab showed rapid improvement by Week 5 in patient reported outcomes in adults and children with PFS, which was sustained through Week 16. References Savic S. and Wood P. Clin. Med. 2011;11(4):396–401 Dandekar P, et al. Pediatr. Rheumatol. 13(S1):P22 Dandekar P, et al. Pediatr. Rheumatol. 13(S1):P23 Dandekar P, et al. Pediatr. Rheumatol. 13(S1):P24 Brik R, et al. Arthritis Rheumatol. 2014;66(11):3241–3 Arostegui, J.I, et al. Arthritis Rheumatol. 2015; 67 (S10) Gattorno M, et al. Arthritis Rheumatol. 2015; 67 (S10) Users manual for the SF-12v2 Health Survey, 3rd ed. 2012 Cohen J, et. al. Statistical Power Analysis for the Behavioural Sciences,2nd ed. 1988 Disclosure of Interest H. Lachmann Consultant for: Novartis, SOBI, Takeda, GSK, Speakers bureau: Novartis, SOBI, A. Simon Grant/research support from: CSL Behring, Novartis, Xoma/Servier, 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, 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, E. Ben-Chetrit Consultant for: Novartis, H. Hoffman Grant/research support from: Bristol Myers Squibb, Consultant for: Novartis, Sob Biovitrum, Regeneron, Speakers bureau: Novartis, A. Zeft: None declared, Y. Joubert Employee of: Novartis, K. Lheritier Employee of: Novartis, A. Speziale: None declared, G. Junge Employee of: Novartis, J. Gregson Employee of: Novartis, F. De Benedetti Grant/research support from: Pfizer, Abbvie, Roche, Novartis, Novimmune, BMS

A Next Generation Sequencing approach to the mutational screening of patients affected with systemic autoinflammatory disorders: diagnosis improvement and interpretation of complex clinical phenotypes

Systemic autoinflammatory diseases (SAIDs) are a group of monogenic disorders characterized by inflammation which occurs in the absence of pathogenic auto-antibodies, auto-reactive T lymphocytes or other infective causes. More than 50% of SAID patients recruited to our Unit does not show any mutation at gene(s) tested by direct Sanger sequencing in the routine diagnosis. Clinical misdiagnosis, mutations in untested gene regions and genetic heterogeneity are possible explanations.

B cells characterization in ADA2 Deficiency patients

ADA2 deficiency, a recently described disease, is characterized by systemic vasculopathy and episodes of strokes. The defect is due to a loss of function mutation of CECR1 gene, codifying for Adenosine Deaminase 2 protein. This protein regulates the catabolism of extracellular adenosine, which we have recently shown is an important regulator of Class Switch Recombination in B lymphocytes. Accordingly DADA2 patients can present hypogammaglobulinemia.