Explore the vast range of titles available.

The anti–interleukin-1 antibody canakinumab was effective at controlling and preventing recurrence of flares in autoimmune inflammatory diseases: familial Mediterranean fever, mevalonate kinase deficiency, and the TNF receptor–associated periodic syndrome.

Computer-assisted reporting (CAR) tools were suggested to improve radiology report quality by context-sensitively recommending key imaging biomarkers. However, studies evaluating machine learning (ML) algorithms on cross-lingual ontological (RadLex) mappings for developing embedded CAR algorithms are lacking. Therefore, we compared ML algorithms developed on human expert-annotated features against those developed on fully automated cross-lingual (German to English) RadLex mappings using 206 CT reports of suspected stroke. Target label was whether the Alberta Stroke Programme Early CT Score (ASPECTS) should have been provided (yes/no:154/52). We focused on probabilistic outputs of ML-algorithms including tree-based methods, elastic net, support vector machines (SVMs) and fastText (linear classifier), which were evaluated in the same 5 × fivefold nested cross-validation framework. This allowed for model stacking and classifier rankings. Performance was evaluated using calibration metrics (AUC, brier score, log loss) and -plots. Contextual ML-based assistance recommending ASPECTS was feasible. SVMs showed the highest accuracies both on human-extracted- (87%) and RadLex features (findings:82.5%; impressions:85.4%). FastText achieved the highest accuracy (89.3%) and AUC (92%) on impressions. Boosted trees fitted on findings had the best calibration profile. Our approach provides guidance for choosing ML classifiers for CAR tools in fully automated and language-agnostic fashion using bag-of-RadLex terms on limited expert-labelled training data.

BackgroundHyper-IgD with periodic fever syndrome (HIDS) is a recessively inherited disorder characterized by periodic episodes of high fever, abdominal distress, joint pain, and skin rashes. Currently, no first line therapy exist to treat HIDS patients, with previous reports have shown heterogeneous outcomes.1,2 IL-1 blockade was reported efficient to reduce the frequency of inflammatory attacks and to improve clinical symptoms.3 We herein report the final results of the study assessing the efficacy and safety of the anti-IL-1β human monoclonal antibody, canakinumab (CAN), in patients with active HIDS.ObjectivesThe primary objective was to assess the reduction of the frequency of flares during the 6-month treatment period compared to a historical treatment-free period. Secondary objectives included assessment of the reduction in the frequency of flares during the 24-month long-term follow-up and an assessment of adverse events (AE) reported during the trial.MethodsThis was an open-label, single treatment arm, efficacy and safety study of SC CAN in patients with active HIDS older than two years. The study duration included a 6-month treatment period with up to 6-month treatment withdrawal period and 24-month long-term treatment period.ResultsAll patients (N=9) enrolled in the study completed the 6-month treatment and the 6-month withdrawal periods with 8 completing the 24-month long-term follow-up. The median number of flares decreased from 5 (3-12) during the historical period to 0 (0-2) during the treatment period. The median remained at 0 (0-3) until the end of the trial. During the long-term period, the median flare duration was 3.5 days (2-8) during the first 12 months and 8.5 days (6-11) during the second year. Flare severity remained “mild” to “moderate” at baseline and decreased to “mild” or “minimal” signs/symptoms and to “mild” or “without” signs/symptoms at the first and second year of the long-term period, respectively. PGA HIDS disease control scores changed in all patients from either “no control” or “poor control” at baseline, to “good” or “excellent control” by day 4 and were maintained at that level until the end of the study. CRP and SAA plasma levels normalized by day 15 and remained normal for the remainder of the study. The most frequent AEs were infections, consistent with that of previous CAN studies. Four patients experienced 14 SAEs (mild to moderate) and none were considered drug-related. Furthermore, there were no AEs leading to discontinuation of study treatment or study overall.ConclusionsCanakinumab markedly reduced the frequency of flares, rapidly alleviated signs and symptoms of acute episodes and normalized the serological inflammatory markers. No AEs lead to study or treatment discontinuation and the safety profile is consistent with other canakinumab studies. These data strongly support a safe and maintained disease control while patients were receiving treatment and reinforce the ongoing development of canakinumab in this therapeutic area.ReferencesDrenth JP, et al. J Pharmacol Exp Ther 2001;298:1221-6.Picco P, et al. Ann Rheum Dis 2001;60:904.Bodar EJ, et al. Neth J Med 2005;63:260-4.Disclosure of InterestJ. I. Arόstegui Grant/research support from: Novartis, J. Anton Grant/research support from: Novartis, Consultant for: Novartis, Speakers bureau: Novartis, I. Calvo Grant/research support from: Pfizer, Abbvie, Novartis, Roche, Speakers bureau: Gebro, Pfizer, Abbvie, Novartis, A. Robles: None declared, A. Speziale Employee of: Novartis, Y. Joubert Employee of: Novartis, G. Junge Employee of: Novartis, J. Yagüe Grant/research support from: Novartis

BackgroundTumor necrosis factor receptor-1 associated periodic syndrome (TRAPS) is a periodic fever syndrome, whose main symptoms are rashes, musculoskeletal and abdominal pain, and periorbital edema. Although TNF inhibitors have been shown to be effective in some patients, their efficacy tends to decrease over time.1-4 Anti-IL-1 treatments have also been used in an effort to provide long term control of the inflammatory manifestations.ObjectivesThe proof of concept study was designed to assess safety, efficacy, and pharmacokinetics (PK) /pharmacodynamic (PD) data upon canakinumab (CAN) and to determine the appropriate dosing for further development of CAN treatment in patients with TRAPS.MethodsThis was an open-label, single treatment arm, efficacy and safety study of monthly CAN 150 mg (2 mg/kg for patient ≤40 kg) SC in patients with active recurrent or chronic TRAPS. Patients were treated for 4-months with a maximum 5-month follow-up period. The initial follow-up period was followed by a maximum 24-month long-term treatment period. The primary efficacy outcome was induction of complete or almost complete response in active TRAPS patients at Day 15 after first CAN dosing.ResultsA total of 20 patients were exposed to study medication, out of which 18 (90%) patients completed the study. Primary endpoint showed that 18 patients [90%; 95% CI: 75.1, 99.9] achieved a complete or almost complete response at Day 15, while 20 (100%) and 12 (60%) patients had clinical and serological remission, respectively (Table). Already at Day 8, 16 patients (80%) achieved a complete or almost complete response, while 18 (90%) and 7 (35%) patients had clinical and serological remission, respectively. A total of 60% of patients experienced study drug-related AEs, most commonly upper respiratory tract infections. Seven patients (35%) experienced SAEs, none of which were related to study drug. Furthermore, there were no deaths during the study.ConclusionsCanakinumab was effective in rapidly alleviating clinical signs and symptoms of TRAPS, whilst normalizing serological inflammatory markers and providing sustained disease control. The safety profile was consistent with previous canakinumab studies in other indications. These data support the ongoing development of canakinumab in this therapeutic area.ReferencesSimon A, et al. Am.J.Med 2004;117:208-10.Weyhreter H, et al. J Pediatr 2003;142:191-3.Jacobelli S, et al. Rheumatology (Oxford) 2007;46(7):1211-2.Arostegui JI, et al. Eur.J.Pediatr 2005;164:13-6.Disclosure of InterestH. Lachmann Grant/research support from: Novartis, Consultant for: Novartis, M. Cattalini Consultant for: Novartis, SOBI, Speakers bureau: Novartis, L. Obici Consultant for: Novartis, Speakers bureau: Novartis, R. Barcellona: None declared, A. Speziale Employee of: Novartis, Y. Joubert Employee of: Novartis, G. Junge Employee of: Novartis, M. Gattorno Grant/research support from: Novartis, SOBI, Speakers bureau: Novartis, SOBI

BackgroundEfficacy and safety of canakinumab (CAN) in frequently flaring difficult-to-treat gouty arthritis (GA) patients (pts) in whom NSAIDs and/or colchicine are contraindicated, not tolerated or ineffective has been published previously. Here, we present the cumulative results from a single long term extension of two phase III studies.ObjectivesTo evaluate the long-term safety and tolerability of CAN. Frequency of new flares, mean number of doses/pt, pts' assessments of GA pain intensity and global assessment (PGA) of response (both on Likert scale) and hsCRP were measured. The efficacy of CAN to maintain urate lowering therapy (ULT) was explored by assessing serum uric acid (SUA) level in pts' initiating or modifying their ULT while exposed to CAN.MethodsAn 18-month, multi-center, open-label, clinical extension study, where all pts upon completing earlier two extension studies continued to be treated with CAN 150 mg for any new GA flare. The treatment groups were analyzed as “CAN Group” [CG] and “TA Group” [TG], i.e. all patients who were initially randomized to receive CAN or TA, respectively, and received at least one dose of study drug. Safety was assessed in terms of exposure-adjusted incidence of adverse events (AEs) per 100 patient-years (pyr). Maximum total cumulative duration was 3 years.ResultsOf the 456 pts randomized in core studies, 136 pts entered and 122 completed E3. Mean flare rate/yr was lower for the CG (1.1) vs TG (2.5). CG pts maintained clinical efficacy (pain intensity and PGA of response to treatment) upon “on demand” retreatment over 3 years. Median hsCRP levels remained below the upper limit normal in pts re-treated with CAN upon demand for new GA flares from 7 days post initial dose over 3 years until end of study. Thirty% (n=12) of pts initiating or modifying ULT during the E3 (n=40) reached target SUA level (<6mg/mL). Overall, the exposure adjusted incidence of AEs in CG was lower (264.6/100 pyr) than in TG (308.8/100 pyr). Re-treatment with CAN did not result in increased incidence of AEs. Overall, the incidence of exposure adjusted SAEs in CG and TG was 17.3 and 17.7 per100 pyr, respectively. The overall incidence of SAEs did not change in pts re-treated with CAN in CG (15.2 vs 15.1 per 100 pyr). Overall 4 deaths, none study drug-related, (2 in CG, 2 in TG), were reported: 1 intracranial hemorrhage [pt not re-treated with CAN]; 1 pneumonia [pt re-treated with CAN], 1 sudden cardiovascular death and 1 pneumococcal sepsis [TG pt who never received CAN]).ConclusionsOver 3 years, CAN mean dose with “on demand” dosing of 2.68 per pt, maintained pain intensity and PGA response scores in difficult to treat GA pts. These results support the long-term safety of CAN treatment in pts' with frequent GA flares. The safety profile was consistent with that observed in previous studies.Disclosure of InterestR. Alten Grant/research support from: Novartis, Speakers bureau: Novartis, T. Bardin Consultant for: Novartis, Astrazeneca, Menarini, Ipsen Pharma, Sobi, M. Bloch Grant/research support from: support to my institution for research: Novartis, Gilead Sciences, ViiV Healthcare, Bristol Myers-Squibb, Merck, Romark, Abbvie, Consultant for: Advisory Board Gilead Sciences, ViiV Healthcare, Bristol Myers-Squibb, Merck, Eli Lilly, Speakers bureau: Eli Lilly, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, U. Machein Employee of: Novartis, G. Junge Employee of: Novartis, A. So Shareholder of: Novartis (<10,000US$), N. Schlesinger Grant/research support from: Novartis, Consultant for: Novartis, Sobi, Speakers bureau: Novartis, Takeda

BackgroundAdult-onset Still's disease (AOSD) is a rare auto-inflammatory disorder resembling a similar pediatric syndrome known as systemic juvenile idiopathic arthritis (SJIA).1 The superimposable systemic and clinical features in SJIA and AOSD suggest that both clinical phenotypes represent a disease continuum with a pediatric (SJIA) and more adult-onset (AOSD). The authors believe that the analyses of gene expression profiles can be useful not only for disease classification, diagnosis, and prognosis, but also to identify disease specific treatment effects that counteract the underlying pathological mechanisms. In the analysis described here, we address the question: How do genes that respond to canakinumab treatment in SJIA patients2 behave in AOSD patients with active disease relative to healthy controls and prior to IL-1 targeting therapy?ObjectivesTo determine how genes that respond to IL-1β blockade with canakinumab in SJIA patients behave in AOSD patients relative to healthy controls.MethodsSJIA gene expression profiles pre- and post canakinumab treatment were compared with AOSD patients relative to healthy subjects using Affymetrix U133Plus 2 DNA microarrays. Expression values of genes are shown for healthy subjects and AOSD patients prior to canakinumab treatment (genes are shown in rows and patient samples in columns).ResultsConsistently, all genes down-regulated in SJIA following canakinumab treatment were upregulated in a majority of AOSD patients with active disease relative to healthy subjects and prior to canakinumab treatment. A few of the AOSD patients resembled healthy subjects (Figure). Comparison of the gene expression patterns to neutrophil counts suggested that elevated neutrophil numbers were closely correlated to the up-regulation of IL-1 associated gene expression.ConclusionsResults are consistent with and further support the concept of a Still's disease continuum that presents as pediatric/juvenile SJIA or adult-onset Still's disease. Moreover, they suggest that AOSD is an IL-1 driven condition that is also mechanistically similar to SJIA and that the observed canakinumab response signature is likely to show a comparable treatment response to IL-1β blockade in AOSD.ReferencesMartini A. Ann Rheum Dis 2012; 71(9):1437-39.Brachat A, et al. Ann Rheum Dis 2014;73(Suppl2): 62.Disclosure of InterestA. Brachat Employee of: Novartis, E. Feist Grant/research support from: Novartis, Consultant for: Novartis, Speakers bureau: Novartis, F. Behrens Grant/research support from: Pfizer, Roche, Abbvie, Chugai, Consultant for: Abbvie, Pfizer, Celgene, Novartis, Chugai, Astra Zeneca, Lilly, Janssen, Merck, Morphosys, Speakers bureau: Abbvie, Pfizer, Celgene, Novartis, Chugai, UCB, Astra-Zeneca, Janssen, Roche, Lilly, N. Blank Grant/research support from: Novartis, SOBI, Amgen, BMS, Pfizer, Roche, Abbvie and others, Speakers bureau: Novartis, SOBI, Amgen, BMS, Pfizer, Roche, Abbvie and others, N. Nanguneri Employee of: Novartis, C. Specker: None declared, M. Witt: None declared, J. Zernicke: None declared, A. Martini Grant/research support from: Abbott, Bristol Myers and Squibb, Francesco Angelini S.P.A., Glaxo Smith & Kline, Janssen Biotech Inc Novartis,Pfizer Inc,Roche,Sanofi Aventis,Schwarz Biosciences GmbH: I declare that the GASLINI Hospital which is the public Hospital where I work as full time employee has received contributions to support the research activities of the network of PRINTO (www.printo.it), Consultant for: Bristol Myers and Squibb, Centocor Research & Development,Glaxo Smith & Kline, Novartis, Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, I declare that the Gaslini Hospital which is the public Hospital where I work as full time employee has received contributions to support the PRINTO research activities from the industries above mentioned., Speakers bureau: Abbott, Abbvie, Amgen, Biogenidecm Bristol MyersSquibb, Astellas, Behringer, Italfarmaco, Janssen, MedImmune, Novartis, NovoNordisk, Pfizer, Sanofi, Roche, Servier., G. Junge Employee of: Novartis

BackgroundGouty arthritis (GA) patients who experience frequent flares and have comorbidities have limited treatment options and need effective alternative treatments. Canakinumab (CAN), a selective, human, anti-interleukin-1β monoclonal antibody, has been approved in the European Union for the treatment of difficult-to-treat GA patients.ObjectivesA liquid formulation of CAN, presented as pre-filled syringe (CAN-PFS) has been developed to improve upon the lyophilized form (CAN-LYO) that requires reconstitution. A cumulative safety and efficacy results covering a total of 48 weeks are presented.MethodsGA patients completing the 12 week core study1 were enrolled in a 36 week open label extension (E1) study. All patients entering E1 received CAN-PFS 150 mg sc on demand upon new GA flare irrespective of assigned treatment during randomization [CAN-PFS, CAN-LYO or triamcinolone acetonide 40 mg (TA)]. The primary objective was to confirm the long-term safety of CAN-PFS vs TA. Secondary objectives included evaluation of CAN-PFS vs TA and CAN-LYO vs PFS for the time to first new flare over 48 weeks. Long-term safety outcomes and safety upon re-treatment were assessed as exposure-adjusted incidence rate of adverse events (AEs) and serious AEs (SAEs).ResultsOf 397 patients randomized in the core study, 232 (58.4%) entered E1, of which 198 (50%) completed E1. Baseline characteristics were comparable between the treatment groups. The exposure-adjusted incidence of AEs was lower for both CAN-PFS (254.9/100 pyr) and CAN-LYO (224.8/100 pyr) groups when compared with TA (362.7/100 pyr) over the 48 weeks. The exposure-adjusted incidence of SAEs was 14.7/100, 16.1/100, 15.5/100 pyr in patients randomized to CAN-PFS, CAN-LYO and TA groups, respectively. Infections and infestations were the most frequently reported SAE in the CAN-PFS (3.4/100 pyr), CAN-LYO (3.2/100 pyr), TA (0/100 pyr) groups. Over 48 weeks, one death (cardiac failure), not suspected to be related to study drug, was reported in a patient randomized to CAN-PFS who was not re-treated over 48 weeks. Overall, no new safety signals were observed in this extension study. CAN-PFS treatment significantly delayed time to first new flare vs TA patients with a relative risk reduction of 55% (HR, 0.45; 95% CI, 0.32 to 0.64; p<0.0001) over 48 weeks. The mean number of new GA flares per patient was lower for both CAN-LYO (0.50) and CAN-PFS (0.76) groups when compared with the TA group (0.96). Patients in the CAN-PFS group had a 56% reduction in the number of new flares compared to the TA group (rate ratio of 0.44, 95% CI 0.32 to 0.61, p<0.0001). However, both CAN treatments showed a similar mean flare rate per year (CAN-PFS, 0.95; CAN-LYO, 1.13).ConclusionsThese results further corroborate the long-term safety and efficacy of canakinumab liquid formulation in patients with frequent GA flares. The safety profile of canakinumab was consistent with the one observed in the core study and the efficacy of canakinumab pre-filled syringe was maintained upon re-treatment.ReferencesSunkureddi P, et al. Arthritis & Rheumatism 2013;65(10):S498.Disclosure of InterestR. Möricke: None declared, P. Sunkureddi Grant/research support from: Novartis, E. Toth: None declared, J. Brown Grant/research support from: Abvie, Amgen, Eli Lilly, Novartis, Pfizer, Roche, Takeda, Consultant for: Amgen, Eli Lilly, Speakers bureau: Amgen, Eli Lilly, U. Machein Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, G. Junge Employee of: Novartis, A. Kivitz: None declared

BackgroundPeriodic 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.ObjectivesPrimary 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.MethodsThe 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).ResultsOf 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).ConclusionsThese 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 InterestF. 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

Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome. VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18–75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895. Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline −1·92 points (95% CI −4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group). The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future. Novartis.

BackgroundPeriodic fever syndromes are a group of rare autoinflammatory conditions that includes, 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). The pharmacokinetics (PK) of canakinumab (CAN) and total interleukin (IL)-1β kinetics have been well characterised in CAPS patients (pts).1 Here we present the PK and pharmacodynamics (PD) of CAN in colchicine resistant/intolerant (crFMF), HIDS/MKD and TRAPS pts.ObjectivesTo evaluate the PK and PD of CAN (solution for injection-liquid in vial [LIVI]) from the phase III study in crFMF, HIDS/MKD and TRAPS pts at Week 16.MethodsThe study (NCT02059291) comprised of 3 disease cohorts (crFMF, HIDS/MKD and TRAPS). Each cohort followed the same study design across 4 epochs (screening epoch [up to 12 weeks], randomised treatment epoch [16 weeks], randomised 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 randomised (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 day15. 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.ResultsIn 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 (AUCtau) was 648±202 μg.day/mL. Similar results were obtained in 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 up titration to 300 mg, levels of total IL-1β were higher suggesting higher production of IL-1β.ConclusionsThis was first study to evaluate the PK characteristics of canakinumab given in the LIVI form. The results observed in crFMF, HIDS/MKD and TRAPS patients were similar to those observed in other indications (CAPS and SJIA) using the lyophilisate form. These data suggested that new formulation did not affect PK/PD of the drug and similarly to CAPS, patients with higher levels of IL-1β may require canakinumab up-titration to have an optimal disease control.ReferencesChakraborty A, et al. Clin Pharmacokinet. 2012;51:e1–18.Disclosure of InterestF. 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, X. Xu Employee of: Novartis