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Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk, and progression, of diabetic kidney disease. We hypothesized that sodium-glucose cotransporter 2 inhibitors could similarly improve the microvascular complication of neuropathy. Methods: The CREDENCE trial randomized participants with type 2 diabetes and albuminuria to canagliflozin or placebo. Neuropathy events were defined as any reported adverse event with a Medical Dictionary for Regulatory Activities (MedDRA) term consistent with peripheral or autonomic neuropathy. The effect of canagliflozin on neuropathy events was calculated by Cox regression. In secondary analyses the endpoint was restricted to sensorimotor polyneuropathy, diabetic neuropathy, or non-autonomic neuropathy events, and subgroups were analysed. P-values adjusted for multiplicity using the Holm-Bonferroni correction were derived for the subgroup analyses. Results: Half (48.8%) of the 4401 participants had a diagnosis of neuropathy at baseline. Over a median of 2.45 years follow up, 657 people experienced a neuropathy event (63.2 per 1000 patient-years). The incidence of neuropathy events was similar in people randomized to canagliflozin and placebo (334/2202 vs. 323/2199; HR 1.04, 95% CI 0.89 to 1.21, p=0.66). Canagliflozin had no impact on sensorimotor polyneuropathy (HR 0.93, 95% CI 0.69 to 1.25, p=0.63), diabetic neuropathy (HR 0.91, 95% CI 0.68 to 1.22, p=0.52), or non-autonomic neuropathy (HR 1.03, 95% CI 0.87 to 1.21, p=0.77). The lack of effect on neuropathy events was consistent in subgroup analyses. Conclusions: Canagliflozin did not affect the risk of neuropathy events in the CREDENCE trial despite clear benefits for nephropathy, cardiovascular disease and glycemic control. Disclosure J. Liao: None. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. A. Levin: Advisory Panel; Self; AstraZeneca, Johnson & Johnson, Research Support; Self; Boehringer Ingelheim International GmbH. D. De zeeuw: Consultant; Self; Boehringer Ingelheim International GmbH, Fresenius Medical Care, Retrophin, Inc., Other Relationship; Self; Bayer Healthcare Pharmaceuticals Inc. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. H. Zhang: None. D. C. Wheeler: Advisory Panel; Self; Merck Sharp & Dohme Corp., Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Janssen Global Services, LLC., Mundipharma International, Tricida, Inc., Speaker’s Bureau; Self; Amgen Astellas BioPharma, Astellas Pharma Inc., Napp Pharmaceuticals, Vifor Pharma Management Ltd. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation, Sanifit, Sanofi, St. Jude Medical. V. Perkovic: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Baxter, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Bristol-Myers Squibb Company, Eli Lilly Japan K. K., Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Novartis Pharmaceuticals Corporation, Novo Nordisk, Pfizer Inc., Retrophin, Inc., Roche Pharma, Sanofi, Servier Laboratories. M. J. Jardine: Advisory Panel; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Intern

Background: Canagliflozin reduces the incidence of kidney and cardiovascular events in people with type 2 diabetes and chronic kidney disease (CKD). We assessed the effects of canagliflozin according to age and sex in a randomized, placebo-controlled trial. Methods: The CREDENCE study randomized participants with type 2 diabetes and albuminuric CKD. The effects of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of the serum creatinine level, or death from kidney or cardiovascular causes), and secondary outcomes were evaluated by age at baseline ( Results: Of the 4401 participants, 33.5%, 42.1%, and 24.4% were Conclusion: Canagliflozin reduces the risk of kidney and cardiovascular events in people with type 2 diabetes and CKD with consistent effects and no differences in safety outcomes across subgroups defined by age and sex. Disclosure T. Yi: None. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. D. De zeeuw: Consultant; Self; Boehringer Ingelheim International GmbH, Fresenius Medical Care, Retrophin, Inc., Other Relationship; Self; Bayer Healthcare Pharmaceuticals Inc. H. L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook, CSL Behring, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, LLC, Merck & Co., Inc., Mitsubishi Corporation Life Sciences Limited, Mundipharma International, Novo Nordisk, Retrophin, Inc., Research Support; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Research & Development, LLC. A. Levin: Advisory Panel; Self; AstraZeneca, Johnson & Johnson, Research Support; Self; Boehringer Ingelheim International GmbH. B. Neal: Advisory Panel; Self; Abbott, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier Laboratories, Research Support; Self; Janssen Pharmaceuticals, Inc., Merck Schering Plough, Roche Pharma, Servier Laboratories. D. C. Wheeler: Advisory Panel; Self; Merck Sharp & Dohme Corp., Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, GlaxoSmithKline plc., Janssen Global Services, LLC., Mundipharma International, Tricida, Inc., Speaker’s Bureau; Self; Amgen Astellas BioPharma, Astellas Pharma Inc., Napp Pharmaceuticals, Vifor Pharma Management Ltd. H. Zhang: None. B. Zinman: Advisory Panel; Self; Abbott Diabetes, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. K. W. Mahaffey: Consultant; Self; Abbott, Amgen Inc., Anthos, AstraZeneca, Baim Institute for Clinical Research, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., CSL Behring, Elsevier, Inova, Intermountain Health, Johnson & Johnson, Medscape, Mount Sinai, Mundipharma International, MyoKardia, National Institutes of Health, Novartis Pharmaceuticals Corporation, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Portola Pharmaceuticals, Inc., Regeneron Pharmaceuticals Inc., SmartMedics, Theravance Biopharma, Research Support; Self; Afferent, AHA, Amgen Inc., Apple, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Cardiva Medical, Inc, Eidos, Ferring Pharmaceuticals Inc., Gilead Sciences, Inc., Google, Johnson & Johnson, Luitpold Pharmaceuticals, Inc., Medtronic, Merck & C

Background: The sodium glucose co-transporter 2 inhibitor canagliflozin reduced the risk of first hospitalization for heart failure (HHF) in the CREDENCE trial. The prevention of recurrent events is important to patients, clinicians and payers. In this post-hoc analysis, we evaluated the effect of canagliflozin on total HHF events. Methods: The CREDENCE trial compared canagliflozin or matching placebo and followed patients for a median of 2.6 years. The study included 4401 participants with type 2 diabetes, substantial albuminuria and estimated glomerular filtration rate (eGFR) 30 to

We tested whether circulating metabolites reflecting cytosolic (lactate/pyruvate) or mitochondrial (β-hydroxybutyrate/acetoacetate [AcAc]) redox balance are associated with major clinical outcomes in patients with type 2 diabetes. The CANVAS study randomized participants to placebo (Plb) or canagliflozin (100mg or 300mg) (Tx) and followed them for up to 6 years. Metabolic markers were measured at baseline (2,373 in Tx [dose combined] and 1,185 in Plb), at year 1 (2,022 in Tx and 949 in Plb) and year 2 (1,793 in Tx and 834 in Plb). By linear mixed model analysis, plasma free fatty acids, AcAc, and β-hydroxybutyrate increased with Tx vs. Plb, whereas plasma pyruvate decreased with Tx while glycerol and lactate did not change significantly. Of note, these changes were independent of the background antihyperglycemic medication (metformin, sulfonylureas, insulin, or combinations thereof). The incidence of hospitalized heart failure or cardiovascular death (HHF/CVD) was 10.2%, the incidence of the renal composite endpoint (CombR; i.e., 40% reduction in eGFR or renal replacement/death) was 3.9%. In Cox models adjusting for sex, age, BMI, HbA1c, baseline systolic blood pressure, diabetes duration, smoking, baseline use of diuretics or statins, history of heart failure, prior CV disease, and Tx, baseline AcAc was a negative predictor of HHF/CVD (HR=0.83 [95%CI 0.75-0.94]), while baseline lactate was a positive predictor (HR=1.42 [95%CI 1.20-1.68]). Adding baseline ACR and eGFR to the same multivariate model for CombR as the outcome, AcAc was still a negative (HR=0.84 [95%CI 0.75-0.94]) and lactate still a positive predictor (HR=1.42 [95%CI 1.20-1.67]). For CV and renal outcomes, higher baseline plasma lactate is an independent positive risk marker potentially reflecting a reducing cytosolic redox shift, but higher baseline plasma AcAc is a protective factor, which may be related to efficient mitochondrial supply/usage of reducing equivalents. Further analysis is needed to test these hypotheses. Disclosure E. Ferrannini: Consultant; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Oramed Pharmaceuticals. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc. S. Baldi: None. T. Scozzaro: None. F. Tesfaye: Employee; Self; Janssen Research & Development, LLC. W. Shaw: Employee; Self; Janssen Pharmaceuticals, Inc. N. Rosenthal: None. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. V. Perkovic: Other Relationship; Self; See Other Relationship field. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. Funding Janssen Research & Development, LLC

Background: Canagliflozin (CANA) slows progression of chronic kidney disease (CKD) in people with type 2 diabetes. CANA also induces a reversible acute decline in estimated glomerular filtration rate (eGFR), which is believed to be a hemodynamic effect. Predictors of the initial decline and its association with long-term eGFR trajectories and safety outcomes are unknown. Methods: This post-hoc study of the CREDENCE trial included 4289 patients with type 2 diabetes and CKD who had eGFR measured at both baseline and week 3. Participants were categorized by percentage decline in eGFR at week 3: >10%, ≤10% to >0%, and ≤0%. Baseline characteristics associated with acute eGFR declines >10% were evaluated using logistic regression. Long-term eGFR decline and safety outcomes were estimated in each eGFR decline category by linear mixed effects models and Cox regression after adjustment for laboratory measures and medication use. Results: More participants in the CANA (956 [45%]) versus placebo (PBO) group (450 [21%]) had an acute eGFR decline >10% (p30% decline occurred infrequently (89 [4%] with CANA and 39 [2%] with PBO; p10%, respectively (both p for interaction 0.05). Results were consistent when other decline thresholds (>20%) were used and in subgroup analysis by baseline eGFR (30- Conclusions: Although acute eGFR declines >10% occurred in nearly half of all patients following initiation of CANA, the benefit of CANA compared with placebo was observed regardless of the acute eGFR decline and safety profiles were similar. Disclosure M. Oshima: Research Support; Self; Japan Society for the Promotion of Science Program for Fostering Globally Talented Researchers. M.J. Jardine: Other Relationship; Self; See Other Relationship field. R. Agarwal: Other Relationship; Self; AbbVie Inc., Akebia Therapeutics, Amgen, AstraZeneca, Bayer Inc., Bird Rock Bio, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc., Ironwood Pharmaceuticals, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OPKO Health, Inc., Reata, Relypsa, Inc., Sandoz, Sanofi, Takeda Pharmaceutical Company Limited, ZS Pharma. G. Bakris: Consultant; Self; Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. C. Cannon: None. D.M. Charytan: Advisory Panel; Self; Allena Pharmaceuticals, AstraZeneca, Merck & Co., Inc., PLC Medical. Employee; Self; BAIM Institute. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Baim, Amgen, Medtronic/Covidien, Zoll, Fresenius, Daiichi Sankyo, Douglas and London, Eli Lilly, Merck, Gilead, and Novo Nordisk. D. de Zeeuw: Advisory Panel; Self; AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. R. Edwards: Employee; Self; Janssen. T. Greene: Other Relationship; Self; Janssen, Durect, and Pfizer. A. Levin: Consultant; Self; Janssen Pharmaceuticals, Inc. Research Support; Self; AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. C.A. Pollock: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Research Support; Self; Diabetes Australia. Speaker’s Bureau; Self; AstraZeneca, Cipla Inc., MedErgy, Medscape, Mitsubishi Tanabe Pharma Corporation, Novartis AG, Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Other Relationship; Self; Amgen, George Institute for Global Health, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. N. Rosenthal: None. D.C. Wheeler: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Reata. Consultant; Self; AstraZeneca, Bayer AG, GlaxoSmithKline, Janssen Pharmaceuticals, Inc. Speaker’s Bureau; Self; Amgen, Astellas Pharma Inc., Mundipharma International, Napp Pharmaceuticals. H. Zhang: Employee; Self; Renal Division of Peking University First Hospital. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. V. Perkovic: Other Relationship; Self; See Other Relationship field. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research & Development, LLC

The benefits of CANA for HF in people with T2D at CV risk appeared to be statistically mediated by erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio (UACR) in the CANVAS Program. CANA reduced the risk of HF in patients with T2D and CKD in CREDENCE. We explored potential mediators of CANA's effects on the composite of hospitalized HF (HHF) and CV death. Mediation analyses are hypothesis-generating observational analyses that calculate the effect of selected biomarkers on the overall treatment effect using time-varying Cox regression. We compared hazard ratios for the effect of randomized treatment from an unadjusted model versus a model adjusted for the average post-randomization level of the biomarker of interest. 62 routine clinical biomarkers and vital sign indicators were collected on all participants and tested as potential mediators. When multiple potential mediators represented a single pathway, those with the strongest univariable mediation were tested in multivariable models. 12 biomarkers, including 3 markers of volume/erythropoiesis (hematocrit [24%], hemoglobin [32%], erythrocytes [27%]), 2 markers of kidney function (UACR [28%], eGFR from wk 3 [7.4%]), and serum albumin (39%), serum protein (24%), lactate dehydrogenase (13%), systolic BP (10%), urine pH (8%), serum urate (7%) and gamma glutamyltransferase (4%), mediated the effect of CANA on HHF/CV death in univariable models. In the multivariable model, hemoglobin, UACR, serum urate and systolic BP maximized cumulative mediation (74%). A diverse set of potential mediators of CANA's effect on HHF/CV death were identified with serum albumin, hemoglobin (or its analogues) and UACR being the most important. The extent to which these mediators reflect underlying inflammatory, nutritional, volume-related or cardiorenal pathways is unclear and underscores the need for further research into the mechanisms of benefit of SGLT2 inhibitors. Disclosure: J. Li: Employee;Self;George Institute. B. Neal: Research Support;Self;Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship;Self;Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. H.L. Heerspink: Consultant;Self;AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. C. Arnott: Employee;Self;George Institute for Global Health. C. Cannon: None. R. Agarwal: Other Relationship;Self;AbbVie Inc., Akebia Therapeutics, Amgen, AstraZeneca, Bayer Inc., Bird Rock Bio, Boehringer Ingelheim Pharmaceuticals, Inc., Celgene, Daiichi Sankyo, Eli Lilly and Company, GlaxoSmithKline plc., Ironwood Pharmaceuticals, Johnson & Johnson, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, OPKO Health, Inc., Reata, Relypsa, Inc., Sandoz, Sanofi, Takeda Pharmaceutical Company Limited, ZS Pharma. G. Bakris: Consultant;Self;Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship;Self;Bayer AG, Novo Nordisk Inc., Vascular Dynamics. D.M. Charytan: Advisory Panel;Self;Allena Pharmaceuticals, AstraZeneca, Merck & Co., Inc., PLC Medical. Employee;Self;BAIM Institute. Research Support;Self;Janssen Pharmaceuticals, Inc. Other Relationship;Self;Baim, Amgen, Medtronic/Covidien, Zoll, Fresenius, Daiichi Sankyo, Douglas and London, Eli Lilly, Merck, Gilead, and Novo Nordisk. D. de Zeeuw: Advisory Panel;Self;AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. T. Greene: Other Relationship;Self;Janssen, Durect, and Pfizer. A. Levin: Consultant;Self;Janssen Pharmaceuticals, Inc. Research Support;Self;AstraZeneca K.K., Boehringer Ingelheim Pharmaceuticals, Inc., Gilead Sciences, Inc. R. Oh: Employee;Self;Janssen Pharmaceuticals, Inc. C.A. Pollock: Advisory Panel;Self;AstraZeneca, Boehringer Ingelheim Pharma euticals, Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Research Support;Self;Diabetes Australia. Speaker's Bureau;Self;AstraZeneca, Cipla Inc., MedErgy, Medscape, Mitsubishi Tanabe Pharma Corporation, Novartis AG, Otsuka Pharmaceutical Co., Ltd., Vifor Pharma Group. Other Relationship;Self;Amgen, George Institute for Global Health, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc. D.C. Wheeler: Advisory Panel;Self;Boehringer Ingelheim Pharmaceuticals, Inc., Reata. Consultant;Self;AstraZeneca, Bayer AG, GlaxoSmithKline, Janssen Pharmaceuticals, Inc. Speaker's Bureau;Self;Amgen, Astellas Pharma Inc., Mundipharma International, Napp Pharmaceuticals. Y. Yavin: Employee;Self;Janssen Research & Development, LLC. H. Zhang: Employee;Self;Renal Division of Peking University First Hospital. B. Zinman: Advisory Panel;Self;Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. G. Di Tanna: Employee;Self;George Institute for Global Health. V. Perkovic: Other Relationship;Self;See Other Relationship field. K.W. Mahaffey: Consultant;Self;Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support;Self;Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. M. Jardine: Other Relationship;Self;See Other Relationship field. Funding: Janssen Research & Development, LLC [ABSTRACT FROM AUTHOR] Copyright of Diabetes is the property of American Diabetes Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Growth differentiation factor 15 (GDF-15) is a marker of inflammation and cellular injury. Small clinical studies have suggested that SGLT2 inhibitors exert anti-inflammatory effects. We examined the association of baseline GDF-15 with kidney outcomes in patients with type 2 diabetes mellitus (T2DM) participating in the CANagliflozin cardioVascular Assessment Study (CANVAS) study. We also assessed the effect of the SGLT2 inhibitor canagliflozin (CANA) on GDF-15. Methods: The CANVAS trial randomized 4330 people with T2DM at high cardiovascular risk to CANA or placebo. Plasma GDF-15 concentration was measured with GDF-15 Roche Elecsys assay at baseline and follow-up. The association between GDF-15 and the primary kidney outcome (40% eGFR decline, end-stage kidney disease, or renal death) was assessed using multivariable adjusted Cox regression. Linear mixed effects models were used to assess the effect of CANA versus placebo on GDF-15 levels. Results: We included 3557 CANVAS participants with available plasma samples (mean age 62.8 years, 33.1% female, mean eGFR 76.9 ml/min/1.73 m2, median uACR 11.6 mg/g, median GDF-15 1776.0 pg/ml). During a mean follow-up of 5.7 years, 137 kidney outcomes occurred. Higher GDF-15 levels were independently associated with higher risk of kidney events (HR 1.98 [95% CI 1.40 to 2.81] per log increment GDF-15). Treatment with CANA modestly lowered GDF-15 compared to placebo (-2% [95% CI -5 to 0; p=0.046]). The effect of CANA on the kidney outcome (HR 0.56, 95% CI 0.40-0.79) was consistent regardless of baseline GDF-15 levels (p-interaction=0.75). GDF-15 did however not mediate the renal protective effect of CANA (percent mediation 3.9% [95% CI -3.6 to 14.0]). Conclusion: CANA modestly lowers GDF-15, which is independently associated with a higher risk of kidney disease progression in patients with T2DM at high cardiovascular risk. The modest reduction in GDF-15 with CANA did not mediate the renal protective effect of CANA. Disclosure J. Li: Employee; Self; George Institute. T. Sen: None. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. B.L. Neuen: Research Support; Self; Australian National Health and Medical Research Council Postgraduate Scholarship, Oxford Australia Clarendon Scholarship from the University of Oxford, University Postgraduate Award from UNSW Sydney. Other Relationship; Self; Janssen Research & Development, LLC. V. Perkovic: Other Relationship; Self; See Other Relationship field. D. de Zeeuw: Advisory Panel; Self; AbbVie Inc., Bayer AG, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Janssen Pharmaceuticals, Inc., Mitsubishi Tanabe Pharma Corporation. K.W. Mahaffey: Consultant; Self; Medscape, Mitsubishi, Myokardia, NIH, Novartis, Novo Nordisk, Portola, Radiometer, Regeneron, SmartMedics, Springer Publishing, UCSF. Research Support; Self; Afferent, Amgen, Apple, Inc, AstraZeneca, Cardiva Medical, Inc, Daiichi, Ferring, Google (Verily), Johnson & Johnson, Luitpold, Medtronic, Merck, NIH, Novartis, Sanofi, St. Jude, Tenax. Y. Yavin: Employee; Self; Janssen Research & Development, LLC. N. Rosenthal: None. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research & Development, LLC

Introduction: Canagliflozin (CANA) slows progression of kidney disease, which may be at least partly mediated by improvements in tubular function. To test this hypothesis, we assessed effects of CANA on markers of tubular function and injury in the CANVAS trial. Methods: Urine biomarkers of tubule function (β2-microglobulin [B2M], cystatin C, and uromodulin), tubular injury (interleukin-18 [IL-18], kidney injury molecule-1 [KIM-1], neutrophil gelatinase associated lipocalin [NGAL], and osteopontin), and inflammation (monocyte chemotactic protein-1 [MCP-1]) were measured at baseline and after 12 months. Biomarker concentrations were standardized for urine creatinine concentration. Differences between CANA and placebo treatment were assessed using ANCOVA models. Results: We included 3723 CANVAS participants with available urine samples (eGFR 77.1 ml/min/1.73 m2 and median UACR 11.7 mg/g). Clinical characteristics and biomarker levels were well balanced between treatment groups at baseline. CANA compared to placebo significantly reduced urinary KIM-1, uromodulin, cystatin C, and osteopontin. It did not change NGAL or MCP-1 and increased IL-18 and B2M. Results were consistent in subgroups by baseline UACR except MCP-1, which decreased in patients with UACR ≥30 mg/g (Table). Conclusion: CANA had variable effects on markers of tubule cell injury and function, decreasing 4, while 2 remained stable and 2 increased. Disclosure T. Sen: None. J. Li: Employee; Self; George Institute. B. Neal: Research Support; Self; Janssen Research & Development, LLC, Merck Schering Plough, Roche Pharma, Servier, Zydus Pharmaceuticals, Inc. Other Relationship; Self; Abbott, Janssen, Novartis, Pfizer, Roche, and Servier. B.L. Neuen: Research Support; Self; Australian National Health and Medical Research Council Postgraduate Scholarship, Oxford Australia Clarendon Scholarship from the University of Oxford, University Postgraduate Award from UNSW Sydney. Other Relationship; Self; Janssen Research & Development, LLC. M.J. Jardine: Other Relationship; Self; See Other Relationship field. J. Ix: Research Support; Self; Baxter. M.G. Shlipak: Advisory Panel; Self; Cricket Health, Tai Diagnostics. V. Perkovic: Other Relationship; Self; See Other Relationshipfield. Y. Yavin: Employee; Self; Janssen Research & Development, LLC. N. Rosenthal: None. M.K. Hansen: Employee; Self; Janssen Research & Development, LLC. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding Janssen Research & Development, LLC

Background:Axial spondyloarthritis (axSpA) is a chronic disease characterised by inflammation in the sacroiliac joints and spine, causing severe back pain and stiffness. Emerging evidence suggests chronic spinal inflammation may be associated with osteoproliferation leading to syndesmophyte formation and spinal ankylosis, with subsequent worsening of patient mobility and function.1Fatty lesions (FLs) on magnetic resonance imaging (MRI) T1 sequences are considered to be post-inflammatory precursors to these changes. Certolizumab pegol (CZP), an Fc-free, PEGylated tumour necrosis factor inhibitor (TNFi), has proven efficacy in treating the signs and symptoms of axSpA.2,3CZP has also been shown to decrease spinal and sacroiliac joint MRI inflammation, and limit radiographic progression of the spine over 4 years of treatment.4Objectives:To report the effect of early post-baseline (BL) inflammatory changes on fatty lesion prevalence over 4 years in a broad axSpA patient population treated with CZP.Methods:RAPID-axSpA (NCT01087762) was a phase 3 trial which was double-blind and placebo (PBO)-controlled to Week (Wk) 24, dose-blind to Wk 48 and open-label to Wk 204. CZP-randomised axSpA patients (Wk 0 CZP: 200 mg every 2 wks [Q2W] or 400 mg Q4W) continued their assigned dose throughout; PBO-randomised axSpA patients (Wk 0 PBO) received CZP from Wk 24, or if non-responders, from Wk 16 onwards. Blinded spinal MRI scans at Wks 0, 12, 48, 96 and 204 were assessed by 2 central readers to evaluate FL and inflammatory lesions in vertebral edges (VEs). Changes in FL prevalence are reported as odds ratios (OR; FL+/FL-) between time points or inflammation states, with nominal 95% confidence intervals (CI), for Wk 0 CZP. ORs were estimated from a logistic regression model for VE level data with random effects for patient and VE (within patient). The fixed model effects included time point, inflammatory status of VEs at BL and Wk 12, FL status at BL, and interactions if appropriate.Results:Of 325 axSpA patients, 89 and 47 initially randomised to CZP or PBO, respectively, had a BL and ≥1 post-BL MRI and therefore were eligible for these analyses. In these patients, a total of 3,127 of VEs were assessed at BL; inflammation was observed in 21.6% and FL in 29.3% of VEs, equating to mean counts of 5.0 and 6.7 per patient; 10.5% of VEs had both inflammation and FL at BL. At BL, FLs were relatively more often observed in inflamed VEs vs non-inflamed VEs: OR (95% CI) of 3.30 (1.94, 5.61). This difference increased over time, as the OR of FL at Wk 204 vs BL was 2.82 (1.70, 4.66) in VEs that were inflamed at BL compared with 1.08 (0.79, 1.48) in VEs that were not inflamed at BL (Figure 1A). Resolution of inflammation by Wk 12 appeared to lower the risk of FL prevalence over 4 years. When adjusted for BL VE status with respect to inflammation and FL, if inflammation prevailed at Wk 12, the OR of FL vs no FL was 1.80 (0.93, 3.49) at Wk 48, 2.54 (1.32, 4.91) at Wk 96 and 3.91 (1.87, 8.15) at Wk 204 (Figure 1B).Conclusion:This is the first report from a clinical interventional PBO-controlled study in a broad axSpA population showing that inflammation that prevailed after the start of TNFi treatment was associated with increased FL prevalence over 4 years. Reduction of inflammation by Wk 12 mitigated the risk of FL over the long-term, indicating the importance of early, effective and long-term treatment targeting inflammation. Similarly, a complete and persistent reduction of inflammation appears to be critical in these patients.References:[1]Maksymowych WP. Ann Rheum Dis 2013;72:23–8;2.Van der Heijde D. Rheumatology (Oxford) 2017;56:1498–509;3.Deodhar A. Arthritis Rheumatol 2019;71:1101–11;4.Van der Heijde D. Ann Rheum Dis 2018;77:699–705.Acknowledgments:This study was funded by UCB Pharma. Editorial services were provided by Costello Medical.Disclosure of Interests:Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Sebastian Kruse: None declared, Simone Auteri Shareholder of: UCB Pharma, Employee of: UCB Pharma, Natasha de Peyrecave Employee of: UCB Pharma, Tommi Nurminen Employee of: UCB Pharma, Thomas Kumke Employee of: UCB Pharma, Bengt Hoepken Employee of: UCB Pharma, Juergen Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Eli Lilly and Company, Medac, MSD (Schering Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi- Aventis, and UCB Pharma, Consultant of: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma

Background:Rheumatoid arthritis (RA) is a chronic inflammatory joint disease potentially leading to disability, impaired functioning, and premature death. Most treatment strategies include the early use of disease-modifying antirheumatic drugs (DMARDs) such as methotrexate (MTX) which is considered as an established ‘anchor’ therapy. Since it takes some weeks until MTX shows clinical efficacy, glucocorticoids (GC) are widely used for bridging.Objectives:The aim of the study “Comparison of the efficacy and safety of two starting dosages of prednisolone in early active RA” (CORRA) is to compare the efficacy and safety of two standard GC bridging schedules vs. placebo in addition to MTX, following a treat-to-target regimen, in early RA.Methods:CORRA is an investigator-initiated, randomised, multi-center, double-blind, placebo-controlled trial. Adult RA patients who were eligible for inclusion in the trial if they had a disease duration of less than 3 years and moderate or high disease activity were recruited in one hospital and 18 rheumatology practices in Germany. Patients were randomised (1:1:1) to receive 60 mg or 10 mg prednisolone (Pred) orally once daily (tapered down to 5 mg Pred within 8 weeks) or placebo. The duration of the intervention was 12 weeks, followed by an open observational phase for another 40 weeks. All patients were also treated with MTX (usually starting with 15mg/week followed by a treat-to target scheme). The primary efficacy endpoint was the progression of the radiographic joint damage after one year compared to baseline as determined by the van der Heijde modification of the Sharp score (SHS). Patients, physicians and readers of radiographs were unaware of the treatment assignments. For the comparison of the two GC groups, a non-inferiority margin of 1.3 points of the SHS was set. This trial was registered at ClinicalTrials.gov, numberNCT02000336.Results:Between February 2014 and February 2017, 395 patients were included in the trial, 381 of which had sufficient data also of follow-up visits. A total of 129 patients were assigned to the 60 mg Pred group, 124 to 10 mg Pred and 128 to the placebo group. At baseline, mean age was 58 years, 58% were female, 55% were rheumatoid factor and 52% ACPA positive. The mean number of swollen joints was 12.8 out of 28, mean ESR was 33.6 mm/h, mean CRP 2.2 mg/dL, mean DAS 28 6.0. Radiographic damage was 4.9 as measured by the SHS. In the 60 mg, 10 mg Pred group and in the placebo group, the DAS 28 was 2.6, 3.1, 4.5 at week 4 (pConclusion:The bridging schedule starting with 60 mg Pred reduced disease activity better than the 10 mg schedule or placebo only for a short time. The primary outcome structural damage was non-inferior in the 10 mg Pred and the placebo group in comparison to the 60 mg Pred group. Initial advantages of the higher dose may have been compromised by the long follow-up with the possible escalation of therapy due to the treat-to-target regimen.Disclosure of Interests:Dietmar Krause Grant/research support from: Pfizer and AbbVie (Abbott), Anna Mai: None declared, Nina Timmesfeld: None declared, Ulrike Trampisch: None declared, Renate Klaassen-Mielke: None declared, Henrik Rudolf: None declared, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Elmar Schmitz: None declared, Claas Fendler: None declared, Claudia Klink: None declared, Stephanie Boeddeker: None declared, Ertan Saracbasi: None declared, Jochen Christoph: None declared, Manfred Igelmann: None declared, Hans Juergen Menne: None declared, Albert Schmid: None declared, Hans J Trampisch: None declared, Juergen Braun Grant/research support from: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, Eli Lilly and Company, Medac, MSD (Schering Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi- Aventis, and UCB Pharma, Consultant of: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma, Speakers bureau: Abbvie (Abbott), Amgen, BMS, Boehringer, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Eli Lilly and Company, Medac, MSD (Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis, and UCB Pharma

SGLT2 inhibitors are approved for glucose lowering in type 2 diabetes (T2DM) and have proven CV benefits, but are not approved for people with significantly reduced kidney function as glycemic efficacy is dependent on glomerular filtration. This analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program assessed effects of canagliflozin on CV outcomes in T2DM according to kidney function (estimated glomerular filtration rate [eGFR] Disclosure B.L. Neuen: Employee; Self; The George Institute for Global Health. T. Ohkuma: None. B. Neal: Research Support; Self; Australian National Health and Medical Research Council Principal Research Fellowship. Other Relationship; Self; Janssen Scientific Affairs, LLC., Roche Pharma, Servier. Research Support; Self; Merck Schering Plough. Advisory Panel; Self; Abbott, Novartis Pharmaceuticals Corporation, Pfizer Inc. D.R. Matthews: Other Relationship; Self; Janssen Scientific Affairs, LLC., Novo Nordisk Inc., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Eli Lilly and Company, Sanofi-Aventis, Servier, Aché Laboratories. D. de Zeeuw: Other Relationship; Self; AbbVie Inc., Astellas Pharma US, Inc., Eli Lilly and Company, Fresenius SE & Co. KGaA, Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Bayer AG, Mitsubishi Tanabe Pharma Corporation. K.W. Mahaffey: Research Support; Self; Afferent, Amgen, AstraZeneca, Daiichi, Ferring, Google (Verily), Janssen, Medtronic, Merck, Novartis, Sanofi, and St. Jude. Consultant; Self; Ablynx, AstraZeneca, BAROnova, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Cubist, Eli Lilly, Elsevier, Epson, GlaxoSmithKline, Janssen, Merck, Mt. Sinai, Radiometer, Springer Publishing, The Medicines Company, Theravance, Vindico, and WebMD. Stock/Shareholder; Self; BioPrint Fitness. G. Fulcher: Other Relationship; Self; Novo Nordisk Inc., Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp. M. Desai: Employee; Self; Janssen Research&Development. Q. Li: Employee; Self; George Institute for Global Health. H. Deng: Employee; Self; Janssen Research&Development. N. Rosenthal: Employee; Self; Janssen Research & Development. M. Jardine: Other Relationship; Self; Fellowships. Research Support; Self; Gambro, Baxter, CSL Behring, Amgen Inc., Eli Lilly and Company, Merck & Co., Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Baxter, Amgen Inc., Roche Pharma. G. Bakris: Other Relationship; Self; Forest Labs, Takeda, Medtronic (15%), Relypsa (15%). Consultant; Self; Takeda, Abbott, CVRx, Johnson&Johnson, Eli Lilly, Food and Drug Administration. Board Member; Self; National Kidney Foundation, American Society of Hypertension. Other Relationship; Self; Editor-Am J Nephrology, HTN ed. UpToDate, Assoc. Ed.- Diabetes Care, Nephrology Dialysis and Transpl. V. Perkovic: Research Support; Self; Australian National Health and Medical Research Council (Senior Research Fellowship and Program Grant). Other Relationship; Self; AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, and Pfizer. Advisory Panel; Self; AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relyps.

Ezetimibe lowers the intestinal absorption of cholesterol, being complementary to the effects of statin. To check its efficacy in lowering the carotid intima-media thickness, in 2002 a multicenter international trial called ENHANCE was started, in order to assess by ultrasound the regression of atherosclerotic plaques. The protocol tested the use of simvastatin 80 mg + placebo versus simvastatin 80 mg + ezetimibe 10 mg in 720 randomized patients. Both drugs were well tolerated. Combination therapy was associated with a larger reduction in LDL cholesterol, but there were no differences in the intima-media thickness measured at three sites in the carotid arteries, nor differences in cardiovascular events between the two groups in the trial. These results provoked disappointment of sponsors (Merck, Schering Plough) who, although the results of the trial were available since march 2007, delayed official communication of about 18 months. This led to speculations and rumors among media, American Government, cardiologic scientific associations, and consequences in the Ezetimibe market and at Wall Street. In particular, the American College of Cardiology didn’t accept the communication of ENHANCE results to the Late Breaking Trial Session of the Chicago congress, diverting it to another secondary forum. In conclusion, the experience of the ENHANCE trial suggests to pharmaceutical companies, researchers, clinicians, scientific companies and media a deep meditation in order to avoid in the future similar problems in the management of results of medical research.

This chapter describes the career in drug discovery of Malcolm MacCoss, from his early studies as a graduate student in the UK and as a postdoctoral fellow in Canada, through his work at Argonne National Laboratory and on to his career at Merck Research Laboratories in Rahway, NJ and eventually to Schering-Plough in Kenilworth, NJ. The particular discoveries of EMEND® and JANUVIA® are discussed.

Introduction Intensive induction chemotherapy for acute myeloid leukemia (AML) in patients aged 60 years or older has lower remission rates with increased induction mortality compared with younger patients. CPX-351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio. Previously reported results from a phase III, randomized, open-label study of CPX-351 versus 7+3 (cytarabine and daunorubicin) in newly diagnosed older patients with secondary AML suggested superior survival in those randomized to CPX-351. We conducted an exploratory analysis of patients who received allogeneic hematopoietic cell transplantation (HCT) after induction treatment, to determine the effect of HCT on outcome by arm, as few patients in this age range can be cured with chemotherapy alone. Methods This phase III trial was a randomized, open-label, parallel-arm, standard therapy-controlled study. Eligible patients were aged 60 to 75 years with newly diagnosed secondary AML defined as having a history of prior cytotoxic treatment, antecedent myelodysplastic syndrome (MDS) (± prior treatment with hypomethylating agents), or AML with World Health Organization-defined MDS-related cytogenetic abnormalities. Patients were randomized 1:1 to CPX-351 induction (100 units/m2 [100 mg/m2 cytarabine + 44 mg daunorubicin mg/m2] on days 1, 3, and 5 [first induction only]) or 7+3 induction (cytarabine 100 mg/m2/day x 7 days plus daunorubicin 60 mg/m2 on days 1, 2, and 3 [first induction] or x 5 days [reinduction/consolidation] plus daunorubicin 60 mg/m2 on days 1 and 2). The distribution of overall survival (OS) after HCT in each treatment arm was estimated using the Kaplan-Meier method, and Cox regression hazard ratio and OS rates, along with corresponding confidence intervals, are reported. Results Three hundred and nine (309) patients were enrolled from December 2012 to November 2014 at 39 US and Canadian sites, with 153 patients randomized to the CPX-351 arm and 156 to the 7+3 arm. Patients in either arm responding to induction with a complete response (CR) or a CR with incomplete platelet or neutrophil recovery (n=125) were considered for allogeneic HCT when possible. In total, 91 patients were transplanted: 52 (34%) from the CPX-351 arm and 39 (25%) from the 7+3 arm. Patient and AML characteristics were similar according to randomized arm, including percentage of patients in each arm that underwent transplant in CR/CRi status (Table); however, the CPX-351 arm contained a higher percentage of older patients (age ≥ 70) who were transplanted (CPX-351, 31%; 7+3, 15%). Mortality at 100 days after transplant was 9.6% for patients in the CPX-351 arm and 20.5% in the 7+3 arm patients. Causes of death Conclusions An exploratory analysis from this phase III study demonstrated that CPX-351, compared with standard cytarabine and daunorubicin, resulted in better outcomes after allogeneic HCT in older patients with high-risk AML, including 53% fewer deaths within 100 days of transplant. These results suggest that CPX-351 may provide an effective bridge to successful transplant for a very poor-risk subgroup of AML patients. Support: Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc. Disclosures Uy: Boehringer Ingelheim: Consultancy; Glycomimetics: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Ritchie:Astellas Pharma: Research Funding; Ariad: Speakers Bureau; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; NS Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding. Stuart:Celator: Research Funding; Incyte: Research Funding; Astellas: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Bayer: Research Funding. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Hogge:Sanofi: Consultancy; Roche: Other: Travel, Accomodations, Expenses. Stone:Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy; Agios: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celator: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Juno Therapeutics: Consultancy; Jansen: Consultancy; Merck: Consultancy; ONO: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy. Kolitz:Gliead Sciences: Consultancy; Pharmacyclics: Consultancy; Seattle Genetics: Consultancy. Schiller:Celator: Research Funding. Ryan:AbbVie: Equity Ownership; U of Rochester: Patents & Royalties. Chiarella:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Medeiros:MEI Pharma: Research Funding; Merck/Schering Plough: Research Funding; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; ARIAD: Consultancy; Celator: Other: Travel, Accomodations, Expenses, Research Funding; Roche/Genentech: Consultancy, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Amgen: Consultancy.

Introduction CPX-351 (Vyxeos), a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio, has shown enhanced efficacy compared with standard induction in older adults with high-risk AML in phase II clinical trials. Presented here are pre-specified secondary subgroup results from a phase III randomized, open-label study of CPX-351 versus 7+3 (cytarabine plus daunorubicin) in newly diagnosed patients with high-risk features, focusing on efficacy results stratified by age group. Methods Eligible patients were aged 60 to 75 years and had secondary AML, either therapy-related or an antecedent myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, or AML with World Health Organization-defined MDS-related cytogenetic abnormalities. Patients were randomized 1:1 to receive CPX-351 induction (100 units/m2 [100 mg/m2 cytarabine + 44 mg daunorubicin mg/m2] on days 1, 3, and 5 [first induction only]) or 7+3 induction (cytarabine 100 mg/m2/day x 7 days plus daunorubicin 60 mg/m2 on days 1, 2, and 3 [first induction] or x 5 days [reinduction/consolidation] plus daunorubicin 60 mg/m2 on days 1 and 2). A dynamic allocation procedure was performed to stratify patients by age group (60-69 or 70-75 years) for each arm of the study. The distribution of overall survival (OS) by treatment arm was estimated using the method of Kaplan-Meier. Efficacy for each age group was reported in terms of median OS in months and percentage of patients with a morphologic complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) according to International Working Group criteria. Results Three hundred and nine patients were enrolled from December 2012 to November 2014 at 39 US and Canadian sites, with 153 patients randomized to the CPX-351 arm and 156 to the 7+3 arm. Among patients aged 60-69 years, there were 96 patients in the CPX-351 arm and 102 in the 7+3 arm; for patients aged 70-75 years, there were 57 and 54 patients in each arm, respectively. Demographic data for these age subgroups were similar between the CPX-351 and 7+3 arms of the study. The CR+CRi rates for patients aged 60-69 years were 50.0% for patients in the CPX-351 arm and 36.3% in the 7+3 arm, with an odds ratio (OR) of 1.76 (95% confidence interval [CI], 1.00-3.10); for patients aged 70-75 years, the rates of CR+CRi were 43.9% and 27.8%, respectively, with an OR of 2.03 (95% CI, 0.92-4.49). Kaplan-Meier curves for OS by age group are shown in the Figure. Median OS in months for patients aged 60-69 years was 9.63 in the CPX-351 arm and 6.87 in the 7+3 arm, with a hazard ratio of 0.68 (95% CI, 0.49-0.95); for patients aged 70-75 years these were 8.87 for the CPX-351 arm and 5.62 for the 7+3 arm, with a hazard ratio of 0.55 (95% CI, 0.36-0.84). The allogeneic hematopoietic cell transplant (HCT) rate in patients aged 60-69 years was 37.5% in the CPX-351 arm and 32.4% in the 7+3 arm, with an OR of 1.25 (95% CI, 0.70-2.25). For patients aged 70-75 years, the allogeneic HCT rates were 28.1% and 11.1%, respectively, with an OR of 3.12 (95% CI, 1.12-8.72). Incidence of grade 3-5 adverse events were virtually equal (92% vs 91%) and were similar in frequency and severity in both arms. The most common grade 3-5 nonhematologic adverse events (>10% overall) were febrile neutropenia (CPX-351: 68%; 7+3: 71%), pneumonia (CPX-351: 20%; 7+3: 15%), and hypoxia (CPX-351: 13%; 7+3: 15%). Conclusions This subgroup analysis of patients aged 60-69 and 70-75 years with untreated secondary AML demonstrated that CPX-351 treatment had substantially greater median OS and higher CR+CRi rates than standard 7+3 (cytarabine and daunorubicin) in both age groups. In addition, somewhat more patients in each age group in the CPX-351 arm received allogeneic HCT compared with the 7+3 arm, with the greatest difference in the older age group. Future studies with larger patient groups are warranted. Support: Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc. Disclosures Medeiros: Agios: Consultancy, Research Funding; Amgen: Consultancy; ARIAD: Consultancy; Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy, Research Funding; Celator: Other: Travel, Accomodations, Expenses, Research Funding; MEI Pharma: Research Funding; Merck/Schering Plough: Research Funding. Lancet:Celgene: Consultancy, Research Funding; Quantum First: Consultancy; Kalo Bios: Consultancy; Pfizer: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; ERYtech: Consultancy; Biopath Holdings: Consultancy; Karyopharm: Consultancy; Boehringer-Ingelheim: Consultancy; Seattle Genetics: Consultancy; Baxalta: Consultancy; Amgen: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Stuart:Astellas: Research Funding; Incyte: Research Funding; Agios: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Bayer: Research Funding; Celator: Research Funding. Strickland:Sunesis Pharmaceuticals: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Celator: Research Funding; Astellas Pharma: Research Funding; Alexion Pharmaceuticals: Consultancy; Sanofi: Research Funding; CTI Biopharma: Consultancy; Karyopharm Therapeutica: Research Funding; Baxalta: Consultancy; Daiichi Sankyo: Consultancy; Ambit: Consultancy; Abbvie: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding. Hogge:Sanofi: Consultancy; Roche: Other: Travel, Accomodations, Expenses. Stone:ONO: Consultancy; Xenetic Biosciences: Consultancy; Seattle Genetics: Consultancy; Amgen: Consultancy; Agios: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Juno Therapeutics: Consultancy; Celator: Consultancy; Roche: Consultancy; Sunesis Pharmaceuticals: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Jansen: Consultancy. Kolitz:Gliead Sciences: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Schiller:Celator: Research Funding. Ryan:AbbVie: Equity Ownership; U of Rochester: Patents & Royalties. Chiarella:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Louie:Celator Pharmaceuticals, Inc., a subsidiary of Jazz Pharmaceuticals plc.: Employment, Equity Ownership. Uy:Glycomimetics: Consultancy; Boehringer Ingelheim: Consultancy.

Background RA leads to high burden on patient (pt) work, functioning and quality of life. Certolizumab pegol (CZP)+MTX improves physical function,1 and workplace and household productivity,2,3 in established and early active RA. Here we report impact of maintaining, reducing frequency or stopping CZP from Week (Wk) 52 to 104 in pts who achieved sustained low disease activity (sLDA) following 1 year (yr) of CZP+optimized MTX. Objectives To assess effect of 2 dosing frequencies of CZP+MTX vs stopping CZP on physical function and workplace/household productivity in Period 2 of C-EARLY, a phase 3 study in early RA pts with severe progressive disease. Methods CZP+MTX-treated pts achieving sLDA (DAS28[ESR]≤3.2 at Wks40 and 52) in C-EARLY Period 1 (NCT01519791)4 entered Period 2 (NCT01521923), a randomized, double-blind study. Pts were randomized 2:3:2 to CZP standard dose (200mg Q2W+MTX), CZP reduced-frequency dose (200mg Q4W+MTX) or CZP stopped (PBO+MTX). Physical function (HAQ-DI) and %pts achieving normative physical function (HAQ-DI≤0.5) from Wk52 to 104 are reported (ANCOVA model with factors treatment, region, time since diagnosis at BL [≤4 vs >4 months], and BL/Wk52 values as covariate and logistic regression models [treatment, region and time since diagnosis at BL as factors] respectively; CZP stopped as comparator; LOCF). Workplace/household productivity (Work Productivity Survey, WPS)5 at Wk52 and 104 are reported (LOCF); non-parametric bootstrap-t method (CZP stopped as comparator). Results In Period 2, 289 pts were included in the full analysis set: CZP Q2W+MTX (n=84), CZP Q4W+MTX (n=126) or PBO+MTX (n=79). Improvements in physical function were maintained from Wk52 to 104 in CZP Q2W+MTX (HAQ-DI mean [SD] 0.32 [0.42] to 0.37 [0.48], respectively) and CZP Q4W+MTX (0.33 [0.49] to 0.41 [0.57]), whereas deterioration was seen in PBO+MTX (0.33 [0.47] to 0.57 [0.65]). %pts with normative function was generally maintained between Wk52 to 104 in CZP Q2W+MTX (80.7% to 71.4%) and CZP Q4W+MTX (80.2% to 70.6%), but decreased in PBO+MTX pts (75.9% to 57.0%). At Wk104, employed CZP Q2W+MTX and CZP Q4W+MTX pts maintained on average the improvements in workplace productivity, whereas worsening was seen in pts stopping CZP (Table). Similar trends were observed in household productivity and need for regular assistance (Table). Conclusions Pts continuing CZP treatment (both dose frequencies) after 1yr further maintained improvements at 2yrs in physical function and workplace/household productivity, compared with pts who stopped CZP. References Strand V. Arthritis Res Ther 2009;11:R170; Kavanaugh A. Arthritis Care Res 2009;61(11);1592–1600; Emery P. Ann Rheum Dis 2015;74(S2);712; Weinblatt M. Arthritis Rheumatol. 2015;67(S10); Osterhaus J. Arthritis Res Ther 2009;11:R73 Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest C. Bingham Consultant for: UCB Pharma, P. Emery Consultant for: Bristol-Myers Squibb, Pfizer, MSD, AbbVie, UCB Pharma, Roche, Schering Plough, Novartis and Samsung, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma, G.-R. Burmester Consultant for: AbbVie, MSD, Pfizer, Roche and UCB Pharma, D. Furst Grant/research support from: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, Consultant for: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, X. Mariette Grant/research support from: Pfizer, GlaxoSmithKline and Roche. Consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, UCB Pharma and Sanofi-Aventis, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB Pharma, Vertex, B. VanLunen Employee of: UCB Pharma, O. Purcaru Employee of: UCB Pharma, V. Bykerk: None declared

Background C-EARLY (NCT01519791) assessed the efficacy and safety of certolizumab pegol (CZP)+optimized MTX vs placebo (PBO)+optimized MTX in inducing and maintaining a sustained clinical response, and inhibiting radiographic damage, in DMARD-naive patients (pts) with active, severe, progressive RA. 1 Here, we examine the association between an inadequate response to PBO+MTX or CZP+MTX treatments at Week (Wk) 12 (lack of improvement from baseline [BL] in DAS28[ESR], DAS28[CRP] or CDAI) and corresponding response at Wk 52. Objectives To examine the association between Wk12 response and Wk52 clinical response (remission [REM]/low disease activity [LDA]) in recently diagnosed DMARD-naive pts with active, severe, progressive RA, treated with CZP+optimized MTX vs PBO+optimized MTX. Methods This multicenter, double-blind, randomized controlled trial enrolled pts who were DMARD-naive with active, severe, progressive RA ( Results The NPV of Wk12 responses were high (Table): PBO+MTX pts who did not achieve DAS28(ESR) improvements from BL ≥0.6 had 94% probability of not being in REM or LDA at Wk52. CZP+MTX pts who did not achieve DAS28(ESR) improvements from BL ≥1.2 had 93% probability of not being in REM at Wk52. NPV of changes in DAS28(CRP) and CDAI at Wk12 were less informative for predicting remission at 1yr (Table). Conclusions In early RA pts treated with optimized-dose MTX, failure to achieve a ≥0.6 DAS28(ESR) reduction from BL at Wk12 was associated with a low probability (6%) of DAS28(ESR) REM/LDA at Wk52, supporting treatment step-up at 3 months. For pts with active, severe RA with poor prognostic factors where CZP has been initiated as first-line treatment, failure to achieve a rapid decrease of 1.2 points was associated with a reduced likelihood of achieving REM (7%). These findings in DMARD-naive pts are consistent with the negative predictability outcomes for CZP in established RA. 2 References Weinblatt M. Arthritis Rheumatol 2015;67(S10); van der Heijde D. J Rheumatol 2012;39:1326–33 Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest X. Mariette Grant/research support from: Pfizer and GlaxoSmithKline., Consultant for: Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, UCB Pharma and Sanofi-Aventis, C. Bingham Consultant for: UCB Pharma, G.-R. Burmester Consultant for: AbbVie, MSD, Pfizer, Roche and UCB Pharma, V. Bykerk: None declared, P. Emery Consultant for: Bristol-Myers Squibb, Pfizer, MSD, AbbVie, UCB Pharma, Roche, Schering Plough, Novartis and Samsung, D. Furst Grant/research support from: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, Consultant for: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Employee of: Director of Imaging at Rheumatology BV, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB Pharma, Vertex, B. VanLunen Employee of: UCB Pharma, C. Arendt Employee of: UCB Pharma, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma

Background MTX plus anti-TNF therapy is an effective treatment for early RA. It is becoming increasingly important to understand whether the dose of anti-TNF can be reduced or stopped in patients (pts) receiving long-term therapy. Objectives To demonstrate that for patients (pts) who achieved sustained low disease activity (sLDA) after 1 year (yr) with CZP 200mg Q2W+optimized MTX, continuation of certolizumab pegol (CZP) as a standard (200mg Q2W) or reduced-frequency dose (200mg Q4W) is superior to stopping CZP for maintaining pts in LDA from Week (Wk) 52 through Wk104. Methods CZP+MTX-treated pts achieving sLDA (DAS28[ESR]≤3.2 at Wks40 and 52) in C-EARLY Period 1 (NCT01519791)1 entered Period 2 (NCT01521923); pts were randomized 2:3:2 to CZP standard dose (200mg Q2W+MTX), CZP reduced-frequency dose (200mg Q4W+MTX) or CZP stopped (PBO+MTX). Pts were evaluated every 8–12 wks. The Period 2 primary endpoint was the proportion of pts who maintained LDA (DAS28[ESR]≤3.2) from Wk52 through Wk104 without flare, using non-responder imputation for missing values. CZP standard dose was compared with CZP stopped; if p The assumptions were that 455 pts would achieve sLDA in C-EARLY Period 1 and enter Period 2, with a response of 95%, 90% and 75% at Wk104 for standard, reduced-frequency and stopped dose respectively. Given α=0.05, there would be 99% and 92% power to detect a difference between CZP standard and reduced-frequency dose vs stopped dose. Results In Period 2, 289 pts (who had achieved sLDA in Period 1) were included in the full analysis set: CZP Q2W+MTX (n=84), CZP Q4W+MTX (n=126) or PBO+MTX (n=79). From Wk52 through Wk104, a greater proportion of pts continuing CZP (either Q2W or Q4W)+optimized MTX maintained LDA vs PBO+MTX (48.8% and 53.2% vs 39.2%; p=0.112 and p Conclusions Early RA pts with prognostic factors for severe disease progression achieving sLDA after 1yr of standard dose CZP+optimized MTX can taper to CZP reduced-frequency dose and maintain comparable disease activity control to CZP standard dose. Pts who stopped CZP had a tendency to have more relapses; despite this, 39.2% of these pts maintained LDA through Wk104. Further work will aim to identify the characteristics of pts who can successfully stop CZP. References Weinblatt M. Arthritis Rheumatol 2015;67(S10) Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest P. Emery Grant/research support from: Bristol-Myers Squibb, Pfizer, MSD, AbbVie, UCB Pharma, Roche, Schering Plough, Novartis and Samsung, C. Bingham Consultant for: UCB Pharma, G.-R. Burmester Consultant for: AbbVie, MSD, Pfizer, Roche and UCB Pharma, V. Bykerk: None declared, D. Furst Grant/research support from: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, Consultant for: Abbott, Actelion, Amgen, Bristol-Myers Squibb, Biogen IDEC, Janssen, Gilead, GlaxoSmithKline, NIH, Novartis, Pfizer, Roche/Genentech and UCB Pharma, X. Mariette Grant/research support from: Pfizer, GlaxoSmithKline and Roche. Consulting fees from Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Roche, UCB Pharma and Sanofi-Aventis, D. van der Heijde Grant/research support from: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Consultant for: AbbVie, Amgen, AstraZeneca, Augurex, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Centocor, Chugai, Covagen, Daiichi, Eli-Lilly, Galapagos, GlaxoSmithKline, Janssen, Merck, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, UCB Pharma and Vertex, Employee of: Director of Imaging at Rheumatology BV, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Pfizer, Roche, UCB Pharma, Consultant for: AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB Pharma, Vertex, B. VanLunen Employee of: UCB Pharma, C. Ecoffet Employee of: UCB Pharma, C. Cioffi Employee of: UCB Pharma, M. Weinblatt Grant/research support from: Amgen, Bristol-Myers Squibb, Crescendo Bioscience and UCB Pharma, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Crescendo Bioscience, Lilly, MedImmune, Merck, Novartis, Pfizer, Roche and UCB Pharma

Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, helps regulate immune responses in psoriatic arthritis (PsA). PALACE 1 compared the efficacy and safety of APR with placebo (PBO) in patients with active PsA despite prior conventional disease-modifying antirheumatic drugs (DMARDs) and/or biologics. Objectives Evaluate the efficacy and safety of APR treatment over 104 weeks. Methods Patients were randomized (1:1:1) to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline DMARD use (yes/no). Patients whose swollen/tender joint counts (SJC/TJC) had not improved ≥20% at Week 16 were considered non-responders and were required to be re-randomized (1:1) to APR20 or APR30 if they were initially randomized to PBO, or continued on their initial APR dose. At Week 24, all remaining PBO patients were re-randomized to APR20 or APR30. Double-blind APR treatment continued to Week 52; patients could continue APR for up to 4 additional years. Results 504 randomized patients received ≥1 dose of study medication (PBO: n=168; APR20: n=168; APR30: n=168). At Week 52, 53.2% of patients receiving APR30 and 59.6% of patients receiving APR20 achieved a modified ACR20 response (Table); $≈ $80% (285/344) of patients completing Week 52 were still receiving APR at the data cutoff during their second year of APR exposure. Patients taking APR demonstrated sustained improvements at Week 104 as shown by modified ACR20/ACR50/ACR70 response rates, SJC/TJC mean percent change, HAQ-DI mean change, proportion of patients with HAQ-DI exceeding the minimal clinically important difference (MCID) ≥0.30 threshold, mean change in DAS-28 (CRP), achievement of DAS (CRP) 52 to ≤104, adverse events (AEs) occurring in ≥5% of APR-exposed patients were nasopharyngitis and upper respiratory tract infection; most AEs were mild/moderate in severity. Diarrhea (1.7%) and nausea (1.2%) occurred at lower rates in Weeks >52 to ≤104 than in Weeks 0 to ≤52 (15.3% and 12.4%, respectively). Serious AEs occurred in 4.7% (APR30) and 6.4% (APR20) of patients over Weeks >52 to ≤104. Fewer discontinuations due to AEs occurred during Weeks >52 to ≤104 (1.5%) vs. Weeks 0 to ≤52 (8.2%). Conclusions Over 104 weeks, APR demonstrated sustained clinically meaningful improvements in signs and symptoms of PsA, including physical function, and associated psoriasis. APR continued to demonstrate an acceptable safety profile and was generally well tolerated. Disclosure of Interest A. Kavanaugh Grant/research support from: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer Inc, Roche, and UCB, A. Adebajo: None declared, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, J. Gomez-Reino Grant/research support from: Roche and Schering-Plough, Consultant for: Bristol-Myers Squibb, Pfizer Inc, Roche, Schering-Plough, and UCB SA, Speakers bureau: Bristol-Myers Squibb, Roche, Schering-Plough, and Wyeth; S. Hall Consultant for: Amgen, AstraZeneca, Boehringer Ingelheim, Centocor, GlaxoSmithKline, MSD, Pfizer, Sanofi Aventis, Sanofi Pasteur, Schering-Plough, Serono, and Wyeth; Paid instructor for: Boehringer Ingelheim, MSD, Roche Schering Plough, Servier, and Wyeth., Speakers bureau: Boehringer Ingelheim, GlaxoSmithKline, MSD, Pfizer, Roche, Sanofi Aventis, Schering-Plough, and Wyeth, E. Lespessailles Grant/research support from: Amgen, Eli Lilly, Novartis, and Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, and Servier, P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Consultant for: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Speakers bureau: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, G. Schett Grant/research support from: Abbott, Celgene Corporation, Roche, and UCB, Consultant for: Abbott, Celgene Corporation, Roche, and UCB, K. Shah Employee of: Celgene Corporation, C. Hu Employee of: Celgene Corporation, J. Wollenhaupt Grant/research support from: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB, Consultant for: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB

Background Apremilast (APR), a phosphodiesterase 4 inhibitor, helps regulate the immune responses in psoriatic arthritis (PsA). PALACE 1-3 compared APR efficacy/safety with placebo (PBO) in patients (pts) with active PsA despite prior conventional DMARDs and/or biologics. Objectives Overall APR safety/tolerability was assessed in a pooled analysis of PALACE 1-3, with APR exposure ≤104 wks. Methods Pts were randomized (1:1:1) to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline DMARD use (yes/no). The PBO-controlled phase continued to Wk 24, with an early escape option at Wk 16. Double-blind APR treatment continued to Wk 52; pts could continue to receive APR during an open-label, long-term treatment phase. We report safety findings from the APR-exposure period (Wks 0 to ≤104). Results 1493 pts were randomized and received ≥1 dose of study medication (PBO: n=495; APR20: n=501; APR30: n=497). A total of 1441 (1209.3 pt-yrs) and 1028 (907.7 pt-yrs) pts received APR in the Wk 0 to ≤52 and Wk >52 to ≤104 periods, respectively. During Wks 0 to ≤52, AEs occurring in ≥5% of APR-exposed pts were diarrhea, nausea, headache, URTI, and nasopharyngitis (Table). Most AEs were mild/moderate in severity during the Wk 0 to ≤104 APR-exposure period; in general, no increase was seen in the incidence/severity of AEs with longer term exposure. During Wks >52 to ≤104, diarrhea (2.9%), nausea (1.8%), and headache (3.0%) occurred at lower rates vs Wks 0 to ≤52 (Table). In Wks 0 to ≤52, 87 pts reported serious AEs (SAEs) vs 71 pts in Wks >52 to ≤104. In few system organ classes, there were numerically more pts reporting SAEs but it did not indicate any specific organ involvement. The vast majority of the SAEs were reported by 1 pt each. There was no increase in cardiac, malignant neoplasm, opportunistic infection, or psychiatric disorder related SAEs and no cases of tuberculosis (new/reactivation) reported with either APR dose. Discontinuations due to AEs occurred at a lower rate (2.3%) during Wks >52 to ≤104. Marked laboratory abnormalities were generally infrequent and most returned to baseline with continued treatment or were associated with a concurrent medical condition. Conclusions APR demonstrated an acceptable safety profile and was generally well tolerated for up to 104 wks, with no new safety concerns identified with long-term exposure. These data continue to support the lack of a need for specific laboratory monitoring with APR. Disclosure of Interest P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Consultant for: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, UCB, Celgene Corporation, Novartis, and Roche, Speakers bureau: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genentech, Janssen, Eli Lilly, Pfizer Inc, and UCB, A. Adebajo: None declared, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Pfizer Inc, Novartis, and UCB, J. Gomez-Reino Grant/research support from: Roche and Schering-Plough, Consultant for: Bristol-Myers Squibb, Pfizer Inc, Roche, Schering-Plough, and UCB SA, Speakers bureau: Bristol-Myers Squibb, Roche, Schering-Plough, and Wyeth, S. Hall Consultant for: Boehringer Ingelheim, MSD, Roche Schering Plough, Servier, and Wyeth., Paid instructor for: Amgen, AstraZeneca, Boehringer Ingelheim, Centocor, GlaxoSmithKline, MSD, Pfizer, Sanofi Aventis, Sanofi Pasteur, Schering-Plough, Serono, and Wyeth, Speakers bureau: Boehringer Ingelheim, GlaxoSmithKline, MSD, Pfizer, Roche, Sanofi Aventis, Schering-Plough, and Wyeth;, A. Kavanaugh Grant/research support from: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer Inc, Roche, and UCB, E. Lespessailles Grant/research support from: Amgen, Eli Lilly, Novartis, and Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, and Servier, G. Schett Grant/research support from: Abbott, Celgene Corporation, Roche, and UCB, Consultant for: Abbott, Celgene Corporation, Roche, and UCB, K. Shah Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, J. Wollenhaupt Grant/research support from: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB, Consultant for: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc, and UCB

Background EULAR recommendations for RA therapy suggest addition of a biologic only if poor prognostic factors such as high disease activity are present. However, low baseline disease activity is associated with better biologic treatment outcomes. Objectives To develop a tool to predict remission/low disease activity (LDA) and aid in selection of patients for anti-TNF treatment. Methods GO-MORE was an open-label, multinational, prospective study in biologic-naive patients (pts) with active RA despite DMARD therapy. Pts received 50-mg subcutaneous golimumab (GLM) once monthly for 6 months along with their background DMARDs. Predictors of 28-joint disease activity score based on ESR (DAS28-ESR) LDA and remission at 6 months were evaluated with univariate and multivariable regression models and receiver operating characteristic (ROC) analyses. To assess the relationship between predicted disease states and observed amount of improvement, further analyses evaluated associations between the final regression model9s predicted rate of remission and observed 6-month improvements in DAS28, Health Assessment Questionnaire (HAQ), and EurolQoL 5-Dimension (EQ-5D). Results 3280 pts were included in the analysis: 82.8% female, mean age 52.3 years, mean disease duration 7.6 years, mean baseline DAS28–ESR 5.97 (standard deviation=1.095). DAS28-ESR remission and LDA were achieved by 23.9% and 37.4% of pts, respectively, after 6 months of GLM therapy. In multiple regression models, remission at 6 months was associated with male sex, absence of comorbidities, and lower age, HAQ, ESR, and tender joint count-28 (TJC28). The final model included sex, comorbidities, age, HAQ, ESR, and TJC28 as continuous variables and had an area under the ROC curve of 0.71 to predict remission and LDA at 6 months. When CRP replaced ESR or SJC28 replaced TJC28, predictive ability was slightly reduced. Predicted remission rates ranged from 4% to 67% in females (figure) and from 7% to 76% in males. Patients who were predicted to be least likely to reach DAS28 remission (who also had the highest baseline disease activity) had the greatest improvements in DAS28, HAQ, and EQ-5D scores during 6 months of GLM treatment. Conclusions Baseline sex, age, ESR, HAQ, absence of comorbidities, and TJC28 were predictive of remission and LDA after 6 months of GLM treatment. Patients with lower likelihood of remission still experienced improvements in DAS28, HAQ, and EQ-5D during treatment. Disclosure of Interest N. Vastesaeger Employee of: MSD Belgium, Brussels, Belgium, P. Durez: None declared, B. Dasgupta Grant/research support from: EULAR, ACR, Health Technology Assessment, British Heart Foundation, Research for Patient Benefits UK, Napp, Consultant for: Schering Plough, Merck, Roche, Mundipharma, Astra Zeneca, B. Combe Consultant for: Merck, H. Schulze-Koops Consultant for: Abbott, Actelion, Biotest, BMS, Chugai, Essex, GSK, MSD, Medac, Merck, Mundai Pharma, Novartis, Nycomed, Pfizer, Roche, UCB, I. Louw Grant/research support from: Merck, BMS, Pfizer, Roche, Janssen, and Lilly, Consultant for: Abbott, BMS, Janssen Pharmaceutica in South Africa, the Merck Investigator Consulting Network, J. Wollenhaupt Grant/research support from: AbbVie, UCB, Pfizer, Sanofi, Astra Pharma, Consultant for: MSD, C. A. Zerbini Grant/research support from: Novartis, Pfizer, Bristol, Lilly, Amgen, MSD, Consultant for: Pfizer, Bristol, Lilly, MSD, A. Beaulieu Grant/research support from: Merck, Servier, Novartis, Amgen, Abbott, Pfizer, Eli Lilly, Roche Centocor, Centocor, Celgene, AbbVie, UCB, Arthrolab, K. Pavelka Consultant for: Amgen, Roche, BMS, MSD, UCB, M. Lazaro Grant/research support from: Bristol Myers Squibb Argentina, Consultant for: Abbott Laboratories, MSD, A. Garcia Kutzbach Grant/research support from: Merck, Janssen, Lilly, Sanofi, Astra Zeneca, R. Moots: None declared, H. Amital: None declared, S. Huyck Employee of: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, B. Fu Employee of: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, M. Govoni Employee of: MSD Italy, Rome, Italy

Introduction Elevated C reactive protein (CRP), a marker of inflammation, is known to correlate with Crohn9s disease (CD) activity 1 2 and to be a predictor of disease relapse in CD. 3 4 However, in patients with moderate or severe CD it is not known whether CRP is associated with disease progression. Methods This post hoc analysis evaluated the association of baseline (BL) CRP and change in CDAI over time in patients with moderate (CDAI >220 to ≤300) to severe (CDAI >300) CD who were randomised to the placebo group in the CHARM trial 5 (N=238). Patients received open-label adalimumab (ADA) induction (week 0: 80 mg; week 2: 40 mg) followed by blinded weekly placebo treatment from weeks 4–56, with switch to open-label ADA allowed after week 12 for disease flare. This analysis grouped patients by CD severity and BL CRP (severe, high: CDAI >300, CRP≥10 mg/l; severe, low: CDAI >300, CRP Results CDAI decreased from BL in all subgroups after ADA induction (Week 4, Abstract PTU-111 table 1). By week 56, the mean CDAI in all subgroups had increased compared with week 4, and was greater in patients who had higher CRP vs lower CRP at BL (244 vs 223, 306 vs 260, for moderate and severe groups, respectively). In patients with moderate CD and high CRP, week 12 and week 56 CDAI approached that of patients with severe CD and low CRP, despite BL differences in CDAI of over 90 points (week 12: 235 vs 243; week 56: 244 vs 260). Conclusion This post hoc analysis of disease activity and CRP demonstrates that an elevated BL CRP in patients with moderate or severe CD is associated with higher disease scores after 1 year. Disease activity over time in patients with moderate CD and higher CRP behaved similarly to that of patients with severe CD and lower CRP. Competing interests J-F Colombel Shareholder with: Intestinal Biotech Development, Grant/Research Support from: Astra-Zeneca, Danisco, Danone, Dysphar, Ferring, Giuliani, Lesaffre, Mapi Naxis, Ocerra Therapeutics, Roquette, Schering-Plough, and UCB, Consultant for: Abbott Laboratories, ActoGeniX NV, Albireo Pharma, Astra Zeneca, Bayer Schering Pharma, Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Centocor, Chemocentryx, Cosmo Technologies, Danone France, Elan, Genentech, Giuliani, Given Imaging, GlaxoSmithKline, Merck, Millennium, NeoVacs, Ocerra, Otsuka American, PDL Biopharma, Pfizer, Ribo Vacs Biotech, Schering-Plough, Shire, Synta, Teva and Petah Tikva, Therakos, UCB, and Wyeth, Speaker bureau with: Abbott Laboratories, Astra Zeneca, Centocor, Elan, Falk, Ferring, Given Imaging, Otsuka American, PDL, Schering-Plough, Shire and UCB, W Sandborn Grant/Research Support from: Centocor Ortho Biotech, Abbott Laboratories, and UCB Pharma, Consultant for: Centocor Ortho Biotech, Abbott Laboratories, UCB Pharma, and Merck (previously Schering Plough), M Castillo Shareholder with: Abbott, Employee of: Abbott, B Huang Shareholder with: Abbott, Employee of: Abbott, Q Zhou Shareholder with: Abbott, Employee of: Abbott, R Thakkar Shareholder with: Abbott, Employee of: Abbott. References 1. Solem C . Inflamm Bowel Dis 2005; 11 :707. 2. Henriksen M . Gut 2008; 57 :1518. 3. Bitton A . Gut 2008; 57 :1386. 4. Consigny Y . Inflamm Bowel Dis 2006; 12 :551. 5. Colombel JF . Gastroenterology 2007; 132 :52.

Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. The PALACE 1, 2, and 3 trials compared the efficacy and safety of APR with placebo (PBO) in patients with active psoriatic arthritis (PsA) despite prior conventional disease-modifying antirheumatic drugs (DMARDs) and/or biologics. Objectives Evaluate the impact of APR over 52 weeks on PsA disease activity. Methods Patients were randomized 1:1:1 to receive PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30) stratified by baseline DMARD use (yes/no). Patients with Results At Week 16, a significantly greater proportion of patients treated with APR achieved a modified ACR20 response vs PBO (primary endpoint). In patients initially randomized to APR and completing 52 weeks, ACR20 response was sustained over 52 weeks. APR20 and APR30 demonstrated improvement in disease activity vs PBO at Week 16, as measured by the DAS-28 (CRP), modified PsARC response, and good or moderate EULAR response. Among patients who were continuously treated with APR through 52 weeks sustained improvements were observed at Week 52 (Table). The most common adverse events reported during the PBO-controlled period (PAL 1-3; pooled) were diarrhea (12.2%), nausea (10.1%), and headache (8.0%). The safety profile of APR through 52 weeks was similar to that observed with APR for up to 24 weeks of treatment (PBO-controlled period). Conclusions APR demonstrated clinically meaningful improvements in measures of PsA disease activity through Week 52. APR demonstrated an acceptable safety profile and was generally well tolerated through 52 weeks. Disclosure of Interest A. Kavanaugh Grant/research support: Abbott, Amgen, Astra-Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor-Janssen, Pfizer Inc., Roche, and UCB, M. Cutolo Grant/research support: Actelion, Bristol-Myers Squibb, and Sanofi-Aventis, Consultant for: Actelion, Bristol-Myers Squibb, and Sanofi-Aventis, P. Mease Grant/research support: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genetech, Janssen, Eli Lilly, Pfizer Inc.,Celgene Corporation, Novartis, Roche and UCB, Consultant for: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genetech, Janssen, Eli Lilly, Pfizer Inc., Celgene Corporation, Novartis, Roche and UCB, Speakers bureau: Abbott, Amgen, Biogen Idec, Bristol-Myers Squibb, Genetech, Janssen, Eli Lilly, Pfizer Inc., and UCB, D. Gladman Grant/research support: AbbVie, Amgen, Bristol-Myers Squibb, Celgene corporation, Janssen, Pfizer Inc., Novartis and UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene corporation, Janssen, Pfizer Inc., Novartis and UCB, A. Adebajo: None declared, J. Gomez-Reino Grant/research support: Roche and Schering Plough, Consultant for: Bristol-Myers Squibb, Pfizer Inc., Roche, Schering Plough, and UCB SA, Speakers bureau: Bristol-Myers Squibb, Roche, Schering Plough, and Wyeth, J. Wollenhaupt Grant/research support: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc., and UCB, Consultant for: Abbott, Bristol-Myers Squibb, MSD, Pfizer Inc., and UCB, G. Schett Grant/research support: Abbott, Celgene Corporation, Roche, and UCB, Consultant for: Abbott, Celgene Corporation, Roche, and UCB, E. Lespessailles Grant/research support: Amgen, Eli Lilly, Novartis, and Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, and Servier, C. Hu Employee of: Celgene Corporation, R. Stevens Employee of: Celgene Corporation, C. Edwards Grant/research support: Celgene Corporation, Pfizer Inc., Roche, and Samsung, Consultant for: Celgene Corporation, Pfizer Inc., Roche, and Samsung, Speakers bureau: Abbott, Glaxo-SmithKline, Pfizer Inc., and Roche, C. Birbara Grant/research support: Bristol-Myers Squibb, Incyte, Eli Lilly, Merck, and Pfizer Inc. DOI 10.1136/annrheumdis-2014-eular.1827

Sir, Following its introduction in the 1980s, buprenorphine (Subutex, Schering Plough) abuse has been reported worldwide.1,,2 Within a year of its introduction to treat opioid dependence in Singapore in 2002, buprenorphine became the second top-selling new pharmaceutical product in 2003, and the fourth best-selling product in 2005.3 This rise in popularity was in turn accompanied by an increase in the number of reported cases …

Background To date no clinical trials are available showing efficacy of moderatly dosed prednisolone for the therapy of active ankylosing spondylitis (AS). Objectives To evaluate the efficacy and safety of moderately dosed prednisolone versus placebo over 2 weeks in patients with active AS despite NSAID treatment. Methods Of 39 patients enrolled, 36 finished the trial. Patients were randomized to one of 3 groups. Prednisolone was given double blind as 20 mg (n=13), 50 mg (n=12) or Placebo (PBO) (n=14) orally every day over 2 weeks. Mean age of the patients was 41 years (range 19-72), mean disease duration was 14 years (range 1-55), HLA-B27 was positive in 71% of patients. Clinical outcome assessments included disease activity (BASDAI), function (BASFI), metrology (BASMI), patient’s global assessment and pain (PG), peripheral joint assessment, Berlin enthesitis score, and C-reactive protein (CRP). Primary endpoint of this study was improvement of BASDAI 50 at Week 2. Results Mean change of BASDAI was significantly higher in the 50 mg group, p=0.026, when compared to PBO whereas this was not the case for the other groups: PBOversus 20 mg, p=n.s., 20 mg versus 50 mg, p=n.s. More patients reached a BASDAI 50 response in the 50 mg versus the PBO group when compared to the other groups, p=n.s. When looked for the 4 BASDAI 50 responders compared to the 8 non responders in the 50 mg group at screening they were significantly younger (35 vs 46 years), had a better spinal mobility (BASMI 2.5 vs. 4.8), higher CRP-values (59 mg/l vs 18 mg/l) lower BASDAI (5.8 vs. 6.6) and a lower BASFI levels (4.4 vs. 8.9). When looked for changes between screening and week 2 within the groups, in the 20 mg group significant improvements were found for BASDAI and pain and in the 50 mg group for BASDAI, BASDAI morning stiffness, BASFI, PG, pain and BASMI (table). Other results are listed in the table below. Conclusions Prednisolone 50 mg showed significantly higher response rates when compared to placebo or 20 mg prednisolone for different outcome parameters in patients with active ankylosing spondyitis. However, 20 mg of prednisolone per day did not show such an effect and the 50 mg high dosis of prednisolone does not seem to be acceptable for a longer treatment period. Disclosure of Interest H. Haibel Grant/Research support from: Merck Germany KgaA, Consultant for: Abbott GmbH, Speakers Bureau: Pfizer, Wyeth Pharmaceuticals, Merck Sharp and Dohme/Schering Plough, Abbott GmbH, C. Fendler: None Declared, J. Listing: None Declared, J. Callhoff: None Declared, J. Braun Grant/Research support from: Pfizer, Wyeth Pharmaceuticals, Merck Sharp and Dohme/Schering Plough, Abbott GmbH, Consultant for: Pfizer, Wyeth Pharmaceuticals, Merck Sharp and Dohme/Schering Plough, Abbott GmbH, UCB, Speakers Bureau: Pfizer, Wyeth Pharmaceuticals, Merck Sharp and Dohme/Schering Plough, Abbott GmbH, UCB, J. Sieper Grant/Research support from: Pfizer, Wyeth Pharmaceuticals, Merck Sharp and Dohme/Schering Plough, Abbott GmbH, Merck Germany KgaA, Consultant for: Pfizer, Wyeth Pharmaceuticals, Merck Sharp and Dohme/Schering Plough, Abbott GmbH, UCB, Speakers Bureau: Pfizer, Wyeth Pharmaceuticals, Merck Sharp and Dohme/Schering Plough, Abbott GmbH, UCB

Objectives In axial spondyloarthritis (SpA) patients (disease duration of Methods Wb-MRIs of 65 patients treated with ETA (n=35) or SSZ (n=30) over 1 year [1,2] and with ETA for the second year were scored for active inflammation, fatty lesions and erosions in the 23 vertebral units (VUs) of the spine and in the 8 SI-joint quadrants by two blinded readers. Here, we analysed chronic lesions (fatty lesions, erosions) in the subgroup treated with ETA continuously over 2 years. Results In total 168 SI-joint quadrants and 437 VUs could be analysed. The mean scores for active inflammation decreased significantly for both the SI-joints and the spine between BL and W(eek) 48, while between W48 and W108 there was no further changes (table 1). In this new reading we could confirm [1] the significant increase of the mean fatty lesion scores between BL and W48 for both the SI-joints and the spine (p Conclusions During continuous treatment with ETA over 2 years in patients with early axial SpA no new chronic lesions (fatty lesions and/or erosions) appeared in the SI-joints or the spine between year 1 and 2. It remains to be determined whether the disappearance of fatty lesions in some of the spinal VU indicates real improvement or just transformation of these lesions into new bone formation. References Song I.-H. et al. Ann Rheum Dis. 2011;70(4):590-6. Song I.-H. et al. Ann Rheum Dis. 2011;70(7):1257-63. Disclosure of Interest I.-H. Song Speakers Bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals: consulting fees or other remuneration. K.-G. Hermann: None Declared, H. Haibel Speakers Bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals: consulting fees or other remuneration. C. Althoff: None Declared, D. Poddubnyy Speakers Bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals: consulting fees or other remuneration. J. Listing: None Declared, A. Weiss: None Declared, E. Lange Employee of: Pfizer Germany, B. Freundlich Employee of: former employee from Pfizer/Wyeth, M. Rudwaleit Speakers Bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals, UCB: consulting fees or other remuneration. J. Sieper Grant/Research support from: Study supported with an unrestricted grant from Pfizer/Wyeth. Speakers Bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals, UCB: consulting fees or other remuneration.

Objectives In patients with early axial spondyloarthritis (SpA) with a disease duration of Methods In the ESTHER trial axial SpA patients were treated with ETN (n= 40) versus sulfasalazine (SSZ) (n= 36) in the first year [1]. After the first year all patients who entered the second treatment year (n= 60) were treated with ETN including 26 patients from the former SSZ group and 22 patients from the former ETN group [2]. Additionally, patients who flared after drug withdrawal at year one and were (re-)treated with ETN (n=12) were also included in this 3 year analysis. Analysis of these 60 patients was performed according to an intention-to-treat analysis which included data for all patients who were still in the study at the beginning of the second year. The four patients who dropped out of the study after the first year in drug-free remission were not counted. Results In the pooled group which was treated over 3 years of ETN (n= 60) the BASDAI decreased from 5.7 (standard deviation 1.3) to 2.6 (2.3), the ASDAS from 3.4 (0.7) to 1.3 (0.6) using an intention to treat analysis. ASAS partial remission after three years was reached by 37%, ASDAS inactive disease by 50% (table 1). 40 of these 60 patients (67%) completed the 3 years of continuous ETN treatment. Conclusions There was a constant and sustained clinical response in patients with early axial SpA patients treated with ETN over 3 years. The response in this early axial SpA cohort seems to be better compared to established AS cohorts with a longer disease duration (> 10 years) where BASDAI50 response rates of 47% after 3 years of infliximab treatment [3] and ASAS partial remission rates of 27% after 4 years of ETN treatment [4] were reported. References Song I.-H. et al. Ann Rheum Dis. 2011;70(4):590-596. Song I.-H. et al. Ann Rheum Dis. 2012;71(7):1212-1215. Braun J. et al. Rheumatology 2005;44:670–676 Davis JC et al. Ann Rheum Dis. 2008;67(3):346-353 Disclosure of Interest I.-H. Song Speakers bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals: consulting fees or other remuneration, K.-G. Hermann: None Declared, H. Haibel Speakers bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals: consulting fees or other remuneration, C. Althoff: None Declared, D. Poddubnyy Speakers bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals: consulting fees or other remuneration, J. Listing: None Declared, A. Weis: None Declared, E. Lange Employee of: employee from Pfizer, Germany, B. Freundlich Employee of: former employee from Pfizer, M. Rudwaleit Speakers bureau: Pfizer/Wy eth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals, UCB: consulting fees or other remuneration, J. Sieper Grant/research support from: research grant from Pfizer/Wyeth, Abott, Speakers bureau: Pfizer/Wy eth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals, UCB: consulting fees or other remuneration

Objectives In patients with early axial spondyloarthritis (SpA) with a disease duration of less than 5 years and evidence of active inflammation on whole-body magnetic reonance imaging (MRI) in the spine and/or the sacroiliac joints (SI-joints) at baseline (BL) (1) we assessed the degree of fluctuation of active inflammation on MRI during treatment with etanercept (ETN). Methods In the ESTHER trial axial SpA patients were treated with ETN (n= 40) versus sulfasalazine (n= 36) in the first year [1]. After one year all patients who continued the study on active treatment were treated with ETN [2]. For this analysis we primarily assessed those patients who were treated with ETN, had active inflammation in the spine and/or SI-joints at BL according to both scorers and of whom complete MRI sets were available from BL, W(eek) 48 and W108. These were 11 patients with evidence for spinal inflammation (253 vertebral units (VUs) assessed) and 25 patients for active sacroiliitis (200 SI-joint quadrants assessed). We also assessed the sites without inflammation at BL compared to W108: there were 15 ETN patients without spinal inflammation at BL (in total 345 VUs). And only 1 patient did not show active sacroiliitis on MRI at BL (in total 8 quadrants). Results More than 70% of active inflammatory lesions in the spinal VUs and the SI-joint quadrants resolved between BL and W48 and between BL and W108 (table 1). New inflammatory lesions developed only in about 2.5% of VUs or SI-joint quadrants (table 1). Similarly, when the SI-joint quadrants and spine VUs without inflammation at BL were analysed, at W108 less than 1% showed new inflammatory lesions: only in 0.9% (3 out of 345) [95% CI: 0.2- 2.5] of VUs new lesions developed. And in no SI-joint quadrant (0% [95% CI: 0-34.0%]) new lesions developed at W48 or W108. Conclusions Nearly no new inflammatory lesions developed during 2 years of etanercept treatment in this early axial SpA cohort. Whether this also prevents the occurrence of bone proliferation has to be proven by longer follow-ups. References Song I-H. et al. Ann Rheum Dis. 2011 Apr; 70(4):590-596. Song I-H et al. Ann Rheum Dis. 2012 Jul; 71(7):1212-1215 Disclosure of Interest I.-H. Song: None Declared, K.-G. Hermann: None Declared, H. Haibel Speakers bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals: consulting fees or other remuneration, C. Althoff: None Declared, D. Poddubnyy Speakers bureau: Pfizer/Wyeth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals: consulting fees or other remuneration, J. Listing: None Declared, A. Weis: None Declared, E. Lange Employee of: employee from Pfizer, Germany, B. Freundlich Employee of: former employee from Pfizer, M. Rudwaleit Speakers bureau: Pfizer/Wy eth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals, UCB: consulting fees or other remuneration, J. Sieper Grant/research support from: research grant from Pfizer/Wyeth, Abott, Speakers bureau: Pfizer/Wy eth Pharmaceuticals, Merck Sharp Dohme/Schering Plough, Abbott Immunology Pharmaceuticals, UCB: consulting fees or other remuneration

Abstract LBA-1 Background: Apixaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for extended treatment of venous thromboembolism. Objectives: To compare the efficacy and safety of two doses of apixaban (2.5 or 5 mg twice daily) with placebo for the extended treatment of venous thromboembolism in patients who have completed 6 to 12 months of prior anticoagulant therapy. Methods: This randomized, double-blind study (ClinicalTrials.gov number, NCT00633893) compared two apixaban doses (2.5 or 5 mg twice daily) with placebo for 12 months in patients with venous thromboembolism who had completed 6–12 months of anticoagulation. The primary efficacy outcome was symptomatic recurrent venous thromboembolism or all-cause mortality. Secondary efficacy outcomes included (a) the composite of symptomatic venous thromboembolism or venous thromboembolism-related death, and (b) the composite of symptomatic venous thromboembolism, venous thromboembolism-related death, myocardial infarction, stroke, or cardiovascular-related death. The primary safety outcome was major bleeding; the secondary safety outcome was major and clinically relevant non-major bleeding. Results: The study included 2486 patients: 829, 840, and 815 randomized to placebo, apixaban 2.5 mg, and apixaban 5 mg, respectively. Rates of the primary efficacy outcome were 11.6% in the placebo group, compared with 3.8% and 4.2% in the apixaban 2.5 mg and 5 mg groups, respectively (absolute risk differences of 7.8% and 7.4%, respectively; 95% confidence intervals 5.3% to 10.3% and 4.8% to 10%, respectively; p Conclusions: Both doses of apixaban reduced the risk of symptomatic recurrent fatal or non-fatal venous thromboembolism by approximately 80% without increasing the rate of major bleeding. In addition, both apixaban doses reduced arterial thrombotic events. The lower apixaban dose may be preferred for extended treatment, because of the trend for less clinically relevant non-major bleeding. Disclosures: Agnelli: Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy; Bayer Healthcare: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Buller:Bayer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi-aventis: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Isis: Consultancy, Research Funding; Thrombogenics: Consultancy, Research Funding. Cohen:Astellas: Consultancy, Research Funding; AstraZenica: Consultancy, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Boheringer-Ingelheim: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mitsubishi Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Portola: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Schering Plough: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Curto:Pfizer: Employment. Gallus:Pfizer: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Bayer: Membership on an entity’s Board of Directors or advisory committees; boehringer-Ingelheim: Membership on an entity’s Board of Directors or advisory committees. Johnson:Pfizer: Employment. Porcari:Pfizer: Employment. Raskob:Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bristol Myer Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Johnson & Johnson: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy; Quintiles: Consultancy; National Blood Clot Alliance: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Weitz:Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

Introduction The CHARM trial 1 demonstrated that adalimumab (ADA) was effective for the maintenance of remission in patients with moderate to severe Crohn9s disease (CD), and that remission rates are influenced by a patient9s baseline C reactive protein (CRP) concentration and prior anti-TNF experience. 1 Patients who were either anti-TNF-naive or had an elevated baseline CRP achieved higher rates of remission than the general study population. In this post hoc analysis we examined whether patients who were anti-TNF-naive and had an elevated CRP at baseline could achieve higher remission rates than those previously reported. Methods Data from CHARM, a 56-week, randomised, placebo-controlled trial of ADA maintenance therapy, were analysed. All patients received open-label ADA during a 4-week induction period, and were then randomised to ADA (40 mg weekly or every other week [eow]) or placebo for a 52-week double-blind period. In this analysis, clinical remission at week 56 was determined for randomised responders (patients who had a decrease in CDAI ≥70 at week 4 compared with baseline) who were naive to prior anti-TNF treatment, by baseline CRP subgroups (high: ≥10 mg/l, vs low: Results ADA treatment (weekly or eow) resulted in statistically significantly greater rates of clinical remission at week 56 compared with placebo treatment in each CRP subgroup of anti-TNF-naive patients (Abstract PTU-110 table 1). The percentage of patients in clinical remission was greater in the high CRP subgroup for both weekly and eow ADA treatment. Conclusion In the CHARM trial, anti-TNF-naive patients with baseline CRP≥10 mg/l experienced greater rates of clinical remission, regardless of ADA dose frequency, compared with patients with baseline CRP Competing interests W Sandborn Grant/Research Support from: Centocor Ortho Biotech, Abbott Laboratories, and UCB Pharma, Consultant for: Centocor Ortho Biotech, Abbott Laboratories, UCB Pharma, and Merck (previously Schering Plough), J-F Colombel Shareholder with: Intestinal Biotech Development, Grant/Research Support from: Astra-Zeneca, Danisco, Danone, Dysphar, Ferring, Giuliani, Lesaffre, Mapi Naxis, Ocerra Therapeutics, Roquette, Schering-Plough, and UCB, Consultant for: Abbott Laboratories, ActoGeniX NV, Albireo Pharma, Astra Zeneca, Bayer Schering Pharma, Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Centocor, Chemocentryx, Cosmo Technologies, Danone France, Elan, Genentech, Giuliani, Given Imaging, GlaxoSmithKline, Merck, Millennium, NeoVacs, Ocerra, Otsuka American, PDL Biopharma, Pfizer, Ribo Vacs Biotech, Schering-Plough, Shire, Synta, Teva and Petah Tikva, Therakos, UCB, and Wyeth, Speaker bureau with: Abbott Laboratories, Astra Zeneca, Centocor, Elan, Falk, Ferring, Given Imaging, Otsuka American, PDL, Schering-Plough, Shire and UCB, M Castillo Shareholder with: Abbott, Employee of: Abbott, Q Zhou Employee of: Abbott, R Thakkar Shareholder with: Abbott, Employee of: Abbott. Reference 1. Colombel JF . Gastroenterology 2007; 132 :52.

Introduction The efficacy of adalimumab (ADA) in Crohn9s disease (CD) by disease duration has been explored, 1 but efficacy and safety of ADA by disease severity have not been investigated. The CHARM 2 and EXTEND 3 trials assessed ADA treatment for the maintenance of remission in patients with moderate to severe CD. Results from CHARM and EXTEND in patients with moderate vs severe CD were pooled to assess efficacy and safety by disease severity. Methods This analysis of pooled data were performed to assess clinical response and clinical remission at week 56 (CHARM) or 52 (EXTEND) in patients with moderate (CDAI ≤300) or severe (CDAI >300) CD, treated with blinded ADA every other week (eow) or placebo. In both trials, patients received open-label ADA induction (CHARM: 80 mg at week 0, 40 mg at week 2; EXTEND: 160 mg at week 0, 80 mg at week 2), followed by blinded treatment (ADA 40 mg eow or weekly, or placebo in CHARM, 40 mg eow or placebo in EXTEND) from weeks 4 to the end of the trial (week 56 in CHARM, week 52 in EXTEND). Data from the ADA 40 mg eow arm of CHARM was pooled with data from EXTEND; safety and efficacy (proportion of patients in clinical remission, defined as CDAI Results A total of 438 patients were included in the pooled analysis: 187 with moderate CD (placebo: 92; ADA: 95) and 251 with severe CD (placebo: 126; ADA: 125). For both moderate and severe CD groups, a statistically significantly greater proportion of patients treated with ADA 40 mg eow achieved clinical response and clinical remission at week 56/52 compared with placebo treated patients (Abstract PTU-109 table 1). The safety profiles in the moderate and severe CD subgroups were similar. Conclusion The analysis of the pooled data from CHARM and EXTEND suggests that ADA 40 mg eow is safe and effective for the treatment of either moderate or severe CD. Competing interests J-F Colombel Shareholder with: Intestinal Biotech Development, Grant/Research Support from: Astra-Zeneca, Danisco, Danone, Dysphar, Ferring, Giuliani, Lesaffre, Mapi Naxis, Ocerra Therapeutics, Roquette, Schering-Plough, and UCB, Consultant for: Abbott Laboratories, ActoGeniX NV, Albireo Pharma, Astra Zeneca, Bayer Schering Pharma, Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Centocor, Chemocentryx, Cosmo Technologies, Danone France, Elan, Genentech, Giuliani, Given Imaging, GlaxoSmithKline, Merck, Millennium, NeoVacs, Ocerra, Otsuka American, PDL Biopharma, Pfizer, Ribo Vacs Biotech, Schering-Plough, Shire, Synta, Teva and Petah Tikva, Therakos, UCB, and Wyeth, Speaker bureau with: Abbott Laboratories, Astra Zeneca, Centocor, Elan, Falk, Ferring, Given Imaging, Otsuka American, PDL, Schering-Plough, Shire and UCB, W Sandborn Grant/Research Support from: Centocor Ortho Biotech, Abbott Laboratories, and UCB Pharma, Consultant for: Centocor Ortho Biotech, Abbott Laboratories, UCB Pharma, and Merck (previously Schering Plough), M Castillo Shareholder with: Abbott, Employee of: Abbott, Q Zhou Employee of: Abbott, R Thakkar Shareholder with: Abbott, Employee of: Abbott. References 1. Schreiber S . Gastroenterology 2007; 132 :A-147. 2. Colombel JF . Gastroenterology 2007; 132 :52. 3. Rutgeerts P . Gastroenterology 2009; 136 :A-116.

Objective: We conducted a randomized phase II study of vandetanib in patients with newly-diagnosed GBM in combination with radiation (RT) and temozolomide (TMZ). Background EGFR and VEGFR signaling have been implicated in the development and growth of GBM. In addition, angiogenesis inhibitors may enhance radiation sensitivity. Vandetanib is an inhibitor of VEGFR-2 and EGFR tyrosine kinase activities. Design/Methods: We planned to randomize a total of 114 newly-diagnosed GBM patients in a ratio of 1:2 to Arm A: RT/TMZ or Arm B: vandetanib 100 mg daily + RT/TMZ. All pts received RT (60 Gy) and concurrent TMZ 75 mg/m 2 daily, followed by adjuvant TMZ for up to 12 cycles (150-200 mg/m 2 on days 1-5 of each 28 day cycle). Pts with age ≥ 18, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS) and safety. Results: We enrolled 106 pts (36 in Arm A, 70 in Arm B) with median age 59 yrs (range: 23-83) and median KPS 90 (range: 60-100). Most frequent Gr ≥ 3 AEs in the vandetanib arm were lymphopenia (20%), thrombosis (12.5%), transaminitis (8%) and leukopenia (5%). Preliminary median OS is 487 days with 95% CI (350, NR) in Arm A and 503 days with 95% CI (451, 634) in Arm B. Median PFS is 141 days with 95% CI (104. 252) in Arm A and 127 days with 95% CI (93. 165) in Arm B. Due to an unplanned interim analysis demonstrating no survival difference, enrollment was terminated early and the study was closed. Conclusions: Although reasonably well-tolerated, the addition of vandetanib to standard chemoradiation in newly-diagnosed GBM may not significantly prolong OS compared to the parallel control arm. Updated efficacy and toxicity data will be presented. Supported by: AstraZeneca. Disclosure: Dr. Lee has received personal compensation for activities with Norvartis and Genentech as an advisory board member.Dr. Lee has received personal compensation in an editorial capacity for UpToDate, Inc. Dr. Batchelor has received personal compensation for activities with Roche Diagnostics Corporation, Genentech, Inc., Merck & Co. Inc., and Millennium. Dr. Batchelor has received personal compensation in an editorial capacity for UpToDate Inc. Dr. Batchelor has received research support from Pfizer Inc, AstraZeneca Pharmaceuticals and Millennium. Dr. Kaley has nothing to disclose. Dr. Schiff has received personal compensation for activities with Novocure and Genentech. Dr. Schiff has received research support from Exelixis. Dr. Lassman has received personal compensation for activities with Schering-Plough Corp., ImClone Systems, Genentech, Inc., Eisai Inc., Cephalon, Inc., Physicians Education Resource, The Robert Michael Educational Institute, and Medical Communications Media.Dr. Lassman has received research support from Keryx Biopharmaceuticals, Genentech, and Schering Plough Corp. Dr. Wong has received research support from AstraZeneca Pharmaceuticals, Exelixis, Novartis and NovoCure as a researcher. Dr. Mikkelsen has received personal compensation for activities with Merck and Roche. Dr. Purow has nothing to disclose. Dr. Drappatz has nothing to disclose. Dr. Norden has nothing to disclose. Dr. Beroukhim has received personal compensation for activities with Novartis as a consultant. Dr. Beroukhim holds stock and/or stock options in AstraZeneca, which sponsored research in which Dr. Beroukhim was involved as an investigator. Dr. Beroukhim holds stock and/or stock options in Baxter, CareFusion, Edwards Lifesciences, and Cardinal Health. Dr. Beroukhim has received research support from Novartis. Dr. Weiss has received personal compensation for activities with a consulting firm as RT expert. Dr. Weiss has received research support from Aposence. Dr. Alexander has nothing to disclose. Dr. McCluskey has nothing to disclose. Dr. Gerard has nothing to disclose. Dr. Teulings has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Muzikansky has nothing to disclose. Dr. Wen has received personal compensation for activities with Merck & Co., and Novartis as consutant and/or speaker. Dr. Wen has received personal compensation in an editorial capacity for UptoDate. Dr. Wen has received research support from Amgen Inc, AstraZeneca Pharmaceuticals, Eisai Inc, Exelixis, Genentech, Inc., Medimmune, Merck & Co., Novartis, Sanofi-Aventis Pharmaceuticals and Vascular Biogenics.