Eric Nantz

Predictors of premature discontinuation of treatment in multiple disease states

Background: Premature discontinuation of treatment impacts outcomes of clinical practice. The traditional perception has been patient discontinuation is mainly driven by unwanted side effects. Systematic analysis of data from clinical trials across several disease states was performed to identify predictors of premature discontinuation during clinical interventions. Methods: A post hoc analysis was conducted on 22 randomized, double-blind, placebo-controlled clinical trials for treatment of fibromyalgia, diabetic peripheral neuropathic pain, major depressive disorder, and generalized anxiety disorder. Analyses were conducted on pooled data within each disease state. Results: Lack of early therapeutic response was a significant predictor of patient discontinuation in each disease state. Visit-wise changes in therapeutic response and severity of adverse events were also significant risk factors, with change in therapeutic response having a higher significance level in three disease states. Patients who discontinued due to adverse events had similar therapeutic responses as patients completing treatment. Conclusion: Contrary to the conventional belief that premature treatment discontinuation is primarily related to adverse events, our findings suggest lack of therapeutic response also plays a significant role in patient attrition. This research highlights the importance of systematic monitoring of therapeutic response in clinical practice as a measure to prevent patients’ discontinuation from pharmacological treatments.

Gene Expression and Pharmacodynamic Changes in 1,760 Systemic Lupus Erythematosus Patients From Two Phase III Trials of BAFF Blockade With Tabalumab

To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52‐week, randomized, placebo‐controlled, double‐blind studies in which patients were treated with the BAFF‐blocking IgG4 monoclonal antibody tabalumab.

Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis

To assess the effects of baricitinib on lipid profiles in patients with moderate‐to‐severe rheumatoid arthritis.

Gene Expression and Pharmacodynamic‐Induced Changes in 1,760 SLE Patients from Two Phase III Trials of B Cell Activating Factor Blockade with Tabalumab

To characterize baseline gene expression and pharmacodynamically induced changes in whole blood gene expression in 1,760 systemic lupus erythematosus (SLE) patients from 2 phase III, 52‐week, randomized, placebo‐controlled, double‐blind studies in which patients were treated with the BAFF‐blocking IgG4 monoclonal antibody tabalumab.

42 Gene expression profile from 1,760 sle patients reveals novel complex interferon responsive gene networks

Background and aims RNA profiling was performed on 1760 SLE patients from two, large Phase III clinical trials, ILLUMINATE-1 and −2. SLE was compared to both healthy controls and other autoimmune diseases, including rheumatoid arthritis, psoriasis and psoriatic arthritis. The goals of this study were to characterise gene expression networks in SLE using these large cohorts, and to compare gene expression phenotypes in SLE to healthy controls and other autoimmune diseases. Methods Blood was collected at baseline and RNA was interrogated on all samples using Affymetrix HTA 2.0 microarrays and on select SLE samples using NanoString nCounterTM. Complete demographics, serum IgG anti-dsDNA antibodies, and complement were measured in SLE. Analyses of gene expression and gene pathways were performed. Results Baseline elevation of interferon responsive genes (IRG) was detected in SLE and associated with younger age, elevated anti-dsDNA antibodies, elevated SLEDAI and decreased levels of C3. Significant differences in SLEDAI organ domain involvement between IRG-positive and IRG-negative groups were observed. Elevated expression of IRG, genes involved with B cell and plasma cell biology, and with cell cycling and signalling were detected in SLE. A bimodal expression pattern of IRG was unique to SLE. Substantial heterogeneity of expression of IRG and complex relationships in interferon (IFN) gene networks were observed. Conclusions There was substantial heterogeneity of gene expression in IFN gene networks when examining individual IFN genes and complex relationships were observed among IFN gene networks. Low IFI27 was identified as a novel subtype of IFN signature in SLE.

THU0088 Structural damage progression in patients treated with methotrexate, baricitinib monotherapy or baricitinib + methotrexate based on their level of clinical response in the phase 3 ra-begin study

Background Baricitinib (BARI), an oral inhibitor of Janus kinase (JAK) 1 and JAK 2, is being developed for the treatment of rheumatoid arthritis (RA). RA-BEGIN was a phase 3 double-blind, three-arm multicentre study of BARI administered as monotherapy or in combination with methotrexate (MTX) to patients (pts) with early active RA who had no or limited treatment with DMARDs. Methotrexate (MTX) monotherapy was the active comparator. Objectives To evaluate the proportion of pts with structural damage progression, defined as change from baseline (CFB) greater than the smallest detectable change (SDC) in mTSS at week (wk) 52, depending on their disease state as measured by DAS28-CRP. Methods Pts were classified into two groups based on DAS28-CRP. Group A included pts who achieved sustained DAS28-CRP ≤3.2 at weeks 16, 20 and 24. Pts who did not achieve DAS28-CRP ≤3.2 consecutively at weeks 16, 20 and 24 and pts with missing DAS28-CRP at any of those 3 visits were included in Group B. The proportion of pts with CFB mTSS > SDC at wk 52 was estimated for each treatment arm for the two defined groups of response. The SDC in mTSS in the RA-BEGIN population at wk 52 was 1.4. Missing mTSS at wk 52 were imputed using linear extrapolation based on baseline data and the most recent radiographic data prior to the missed radiograph. No formal statistical tests were performed and comparisons are merely descriptive. All analyses were post-hoc. Results Out of the 584 pts of the modified-ITT population (all randomised pts who received at least 1 dose of study drug) in the RA-BEGIN study, 212 were classified in Group A: 21.4% (45/210), 42.1% (67/159), and 46.5% (100/215) for MTX, BARI and BARI+MTX, respectively. The odds ratios for sustained DAS28-CRP ≤3.2 response (weeks 16, 20 and 24) to BARI and BARI+MTX vs. MTX, were respectively 2.8 (95% CI 1.7–4.4) and 3.3 (95% CI 2.1–5.1). Pts classified in Group A maintained an adequate level of response up to wk 52. Further, pts in Group A (sustained DAS28-CRP ≤3.2) on either BARI + MTX or BARI, were less likely to show structural progression than patients who achieved sustained DAS28-CRP ≤3.2 on MTX. Pts in Group B on MTX or BARI monotherapy were more likely to show structural progression than patients who did not achieve a sustained DAS28-CRP ≤3.2 response on BARI + MTX (Figure 1). Footnote: Group A: Patients who achieved sustained DAS28-CRP ≤3.2 (NRI) at weeks 16, 20 and 24 (N=212); Group B: Complement group Conclusions In patients who achieved sustained low DAS28-CRP scores, progression rates compared to MTX were reduced to a similar degree with BARI as monotherapy or in combination with MTX. Compared to MTX in patients who did not achieve sustained low DAS28-CRP scores, progression rates were reduced most markedly with combination therapy. Disclosure of Interest D. van der Heijde Consultant for: Abbvie, Amgen, Astellas, AstraZeneca, BMS, Boeringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly and Company, Galapagos, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, UCB, P. Durez: None declared, G. Schett: None declared, E. Naredo: None declared, M. Østergaard Consultant for: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, and Wyeth, G. Meszaros Employee of: Eli Lilly & Company, N. Bello Employee of: Eli Lilly & Company, I. De la Torre Employee of: Eli Lilly and Company, P. Lopez-Romero Employee of: Eli Lilly & Company, D. Schlichting Employee of: Eli Lilly and Company, E. Nantz Employee of: Eli Lilly and Company, R. Fleischmann Consultant for: Abbvie, Amgen, Astra Zeneca, BMS, Celgene, Janssen, Eli Lilly and Company, Novartis, Roche, Sanofi-Aventis, Pfizer, UCB

THU0201 Weak Correlation between A Multi-Biomarker Disease Activity Score and Clinical Response with Baricitinib in A Phase 2b Study in Rheumatoid Arthritis:

Background Regular disease activity assessment should be a key component of rheumatoid arthritis (RA) care. In patients with moderate-to-severe RA and inadequate response to methotrexate (MTX-IR) treated with baricitinib (bari) 1, 2, 4, or 8 mg in a Phase 2b double-blind study, bari demonstrated clinically and statistically significant improvements at 12 wks including DAS28-CRP <2.6 for 1 (14%), 2 (15%), 4 (37%), and 8 (22%) mg versus placebo (4%; PBO).1 (Elevated high-sensitivity C-reactive protein (hsCRP) >1.2xULN or erythrocyte sedimentation rate (ESR) >28 mm/h was required at study entry.1) In the same study, only modest, statistically significant improvements in a multi-biomarker disease activity score (MBDA)2 were observed.3 Objectives To investigate how MBDA correlates with clinical endpoints in the previously reported study.3 Methods Post-hoc statistical analysis was conducted on combined bari 1, 2, 4, and 8 mg (n=189) and paired low (1, 2 mg; n=91) and high (4, 8 mg; n=98) doses using partial correlation analyses, which controls for effects of association with other variables, to assess the relationship between MBDA and absolute change from baseline in 13 disease activity measures. Results Mean MBDA improved from baseline to Wk 12 for each dose versus PBO,3 but the two highest correlations were only of moderate strength: hsCRP [a component of MBDA] (r=0.60) and DAS28-CRP (r=0.43). For all other measures, associations with MBDA were significant (p<0.05) but of weak magnitude; swollen joint count (SJC) was not significant (Table). The low- and high-dose pairs had mostly weak correlations (not shown); the strongest correlation was with hsCRP (r=0.50, 0.68, respectively; both p<0.001). Disease activity measures r† hsCRP 0.60** DAS28-CRP 0.43** ESR 0.32** DAS28-ESR 0.27** SDAI 0.27** HAQ-DI 0.24** Patients Global Assessment of Arthritis Pain 0.23** Physicians Global Assessment of Disease Activity 0.23** American College of Rheumatology Change from Baseline (ACR-N)‡ −0.20* Patients Global Assessment of Disease Activity 0.18* TJC (68 joints) 0.17* CDAI 0.16* SJC (66 joints) 0.04 †Pearson partial correlation coefficient (r) assessed relationship between MBDA score and absolute changes from baseline at Wk 12 in the combined dose group. **p≤0.001, *p<0.05. P-value calculation based on Pearson correlation inference test. ‡ACR-N measures % improvement from baseline. Conclusions In MTX-IR patients treated with bari for 12 wks, significant changes in clinical response measures were seen but were not strongly correlated with MBDA. The highest correlations, although statistically significant, were of moderate strength. MBDA score changes did not have a strong correlation to clinical measures with bari. If these observations are corroborated they would suggest that caution is required when assessing clinical response to bari using the MBDA. References Keystone E et al. Ann Rheum Dis 2015;74(2):333–340. Segurado OG, Sasso EH. Clin Exp Rheumatol 2014;32(85):S29-S34. Taylor P et al. Ann Rheum Dis 2015;74(Suppl 2):257–258 as presented at EULAR 2015. Disclosure of Interest R. Fleischmann Grant/research support from: Eli Lilly and Company, Pfizer, Consultant for: Eli Lilly and Company, Pfizer, M. Genovese Grant/research support from: AbbVie, Astellas, Eli Lilly and Company, Galapagos, Pfizer, Vertex, Consultant for: AbbVie, Astellas, Crescendo Bioscience, Eli Lilly and Company, Galapagos, Pfizer, Vertex, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Janssen Inc, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company, Eli Lilly and Company, F. Hoffmann-La Roche Inc, Genentech Inc, Janssen Inc, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Myers Squibb Canada, F. Hoffmann-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Weinblatt Grant/research support from: Crescendo Bioscience, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, Crescendo Bioscience, J. Rancourt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, E. Nantz Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, D. Schlichting Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, S. Zuckerman Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, W. Macias Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, P. Taylor Grant/research support from: Celgene, GlaxoSmithKline, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly and Company, Galapagos, GlaxoSmithKline, Merck, Pfizer, Takeda, USB

A5.10 Increases in serum cholesterol with baricitinib treatment are associated with favourable changes in apolipoprotein content and with improvement in DAS28-CRP in patients with rheumatoid arthritis

Treatment with baricitinib (bari), an oral inhibitor of JAK1/JAK2, demonstrated improvements in signs and symptoms of RA through 52 wks in a Phase 2b study,1 and also in dose- and time-dependent changes in serum lipids, LDL particle size and HDL and VLDL particle numbers.2 Increases in HDL, but not LDL cholesterol, correlated with decreases in CRP at Wk 12. Changes in serum cholesterol, in apolipoprotein content of LDL, VLDL, and HDL particles were evaluated. Patients (pts) with RA were randomised to QD doses of placebo (PBO) (n = 98) or bari 1 mg (n = 49), 2 mg (n = 52), 4 mg (n = 52), or 8 mg (n = 50) for 12 wks. Pts assigned to 2-, 4-, or 8-mg bari continued blinded treatment for an additional 12 wks. Serum samples were collected through 52 wks for conventional lipid determinations (total cholesterol, LDL, HDL, and triglycerides). Apolipoprotein content was assessed at Wks 4 and 12 for PBO, 4-, and 8-mg bari groups. Pts treated with bari through 52 wks maintained a stable cholesterol and triglyceride profile with no further changes beyond Wks 12 and 24. Increases in apolipoprotein A-I, apolipoprotein B, and total apolipoprotein CIII were observed with 4- and 8-mg bari with no increase in LDL-associated apolipoprotein CIII. Bari treatment also demonstrated a significant reduction in HDL-associated SAA at the 4- and 8-mg doses compared to PBO while a significant reduction in Lp (a) was observed only in the 8-mg bari group (all p < 0.05). These changes in apolipoproteins coincided with the increases in serum lipids apparent by Wk 4. In pts treated across all doses of bari, a significant correlation was observed between change in HDL cholesterol and absolute DAS28-CRP score at Wk 12 (r = -0.33, p < 0.001) as well as the change from baseline to Wk 12 in the DAS28-CRP (r = -0.29, p < 0.001). Specifically, pts achieving DAS28-CRP <2.6 and larger decreases in DAS28-CRP demonstrated larger increases in HDL cholesterol. No significant correlations were observed in the PBO arm between HDL and disease activity measures and not between disease activity and total cholesterol or LDL levels in the bari arms. In addition to increases in serum cholesterol and lipoprotein particle number (HDL and VLDL) and size (LDL), there were changes in apolipoprotein content of these particles in pts treated with bari. The increase in HDL cholesterol with bari treatment correlated with an improvement in DAS28-CRP. References Taylor P, Genovese MC, Keystone E, et al . Ann Rheum Dis 2013; 72:A65–A66. Kremer J, Genovese M, Keystone E, et al . Baricitinib effects on serum cholesterol and circulating lipid particles in a Phase 2b study in patients with rheumatoid arthritis [abstract]. Ann Rheum Dis 2013; 72 (Suppl 3):241.

OP0079 Pharmacodynamic Changes in Gene Expression Observed in Two Phase 3 Trials of Baff Blockade with Tabalumab in SLE

Background RNA gene expression profiling was performed on 1,760 SLE patients randomly selected from Illuminate Trials 1 & 2 which studied the anti-BAFF, IgG4 monoclonal antibody, tabalumab, for efficacy in SLE (Isenberg D., et al. ACR Boston 2104). The baseline disease activity and clinical characteristics were balanced across treatment and placebo groups in both Trial 1 (N=1164) & 2 (N=1124). The primary endpoint of SRI-5 was not met in Trial 1 but was met in Trial 2 for the 120mg Q2week (W) dose (p=0.002). Objectives The present study characterized baseline and pharmacodynamic (PD)-induced changes in gene expression from these two cohorts of SLE patients. Methods Whole blood was collected in Tempus tubes at baseline, weeks 16 and 52. RNA was extracted and analyzed using Affymetrix HTA 2.0 whole genome microarrays. Serum levels of IgG anti-dsDNA antibodies (abs) were measured by ELISA. Serum complement components C3 and C4 were measured by nephelometry and B cells enumerated using flow cytometry. Statistical analyses to identify PD-induced gene changes were conducted with Q2W and Q4W cohorts using a mixed effects model with relative gene expression as the response and inclusion of baseline clinical covariates. Results Statistically significant PD changes were observed in both trials in the Q2W and Q4W 120mg dosing arms compared to placebo for the following biomarkers: anti-dsDNA abs, C3 & C4, total serum IgG, IgM & IgA, and peripheral blood B cell number (all with p<0.001). Changes in gene expression in tabalumab treated patients were compared to placebo in 422 randomly selected patients at baseline, weeks 16 and 52. Statistically significant changes were identified in 410 genes (false discovery rate qval<0.20 Trial 1 and p<0.20 Trial 2) including: plasma cell markers, B cell markers, TNF superfamily members, Fc & Fc-like receptors, complement receptors and a pain receptor, SCN3A. There were no changes in monocyte or neutrophil specific markers. A group of 34 pre-specified interferon responsive genes (IRG) were examined and baseline elevation of IRG was significantly associated with elevated anti-dsDNA abs and decreased levels of C3 & C4. B cell number as measured by flow cytometry correlated with gene expression of B cell-associated genes including CD19. PD changes in predefined B cell and plasma cell genes were observed in the treatment groups and associated with changes in anti-dsDNA abs, serum Ig and complement levels, and cell number; however, treatment with tabalumab was not associated with changes in IRG or BAFF gene expression. Conclusions Pharmacodynamic changes associated with tabalumab treatment included anti-dsDNA abs, complement components C3 & C4, serum IgG, IgA & IgM, and B cell numbers. Statistically significant changes were observed in 410 genes, broadly consistent with the mechanism of BAFF blockade. Changes in expression of a number of additional genes were unexpected and suggest that these may be of importance in anti-BAFF drug response. The data here confirm previous smaller studies that a Type I interferon signature may represent a distinctive subset of SLE patients. Disclosure of Interest R. Hoffman Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, J. Merrill: None declared, M. Alarcόn-Riquelme: None declared, M. Petri: None declared, E. Dow Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, E. Nantz Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, L. Nisenbaum Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, K. Schroeder Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, W. Komocsar Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, N. Perumal Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, G. Rocha Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, R. Higgs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company

THU0175 Effects of Baricitinib on Multibiomarker Disease Activity Scores and Their Components in a Phase 2B Study in Moderate-to-Severe Rheumatoid Arthritis Patients

Background Baricitinib, an oral inhibitor of JAK1 and JAK2 signaling, improved the signs and symptoms in patients with active rheumatoid arthritis (RA) who were methotrexate inadequate responders (MTX-IR) in a double-blind, placebo (PBO) controlled study1. Objectives To investigate how a quantitative, multibiomarker disease activity score (MBDA) and its individual components are affected by treatment with baricitinib 4 mg (n=50) once daily compared to PBO (n=79) during a 12 week treatment period in moderate-to-severe RA patients. Methods Serum samples collected at baseline and Weeks 4 and 12 from patients in the study1 were shipped frozen to Crescendo Biosciences for analysis2. MBDA scores and changes in individual MBDA components were subjected to post-hoc statistical analyses. Results At baseline, the proportion of patients with low, moderate, and high MBDA scores were similar in the 2 groups, as were median MBDA scores (PBO=44 vs. baricitinib 4 mg=47). Unlike PBO-treated patients, baricitinib 4 mg patients had decreased MBDA scores at 4 and 12 weeks compared to baseline (baricitinib 4 mg =35.5 and 37.0 (p<0.001) vs. PBO=46.0 and 45.0, respectively). At both 4 and 12 weeks of treatment and compared to PBO, baricitinib-treated patients had significant decreases in MBDA components including C-Reactive Protein (CRP), Matrix metalloproteinase (MMP)-3, serum amyloid A (SAA), soluble TNF receptor (TNF-RI), VCAM-1, and YKL-40 (human cartilage glycoprotein 39). Compared to PBO, there were no significant (p>0.05) changes for baricitinib-treated patients at either timepoint for epidermal growth factor (EGF), MMP-1, or vascular endothelial growth factor-A (VEGF-A). For baricitinib-treated patients versus PBO, at 4 but not 12 weeks, Interleukin-6 (IL-6) and resistin were significantly decreased and at 12 but not 4 weeks, leptin was significantly increased.Table 1 MBDA components, median % change from baseline† Week 4 Week 12 Placebo Baricitinib Placebo Baricitinib (n=79) (n=50) (n=79) 4 mg (n=50) CRP 6.6 −66.9*** 8.2 −56.1*** IL-6 15.3 −28.3*** 4.2 −16.2NS Leptin 8.4 20.6NS 8.7 31.9** MMP-3 4.5 −12.3** 6.3 −14.5*** Resistin −1.2 −12.1** 0.5 −7.6NS SAA 9.9 −56.4*** 9.2 −37.6*** TNF-RI −0.1 −12.1*** 1.2 −12.0*** VCAM-1 1.4 −15.9*** 1.0 −12.1*** YKL-40 −0.5 −26.2*** −1.6 −9.9* †P values vs. PBO determined using pairwise comparison of means for MBDA score and Wilcoxon rank-sum test for % change for components: NS, p>0.05; *p<0.05; **p<0.01; ***p<0.001. Conclusions Consistent with other indices of disease activity1, the treatment of MTX-IR patients with baricitinib 4 mg once daily resulted in a reduction in the MBDA scores, apparent by 4 weeks. Decreases in MBDA scores and the components were present at both 4 and 12 weeks. Reduction in the levels of inflammatory markers beyond those associated with an acute phase response is apparent in these patients. References Keystone E et al., Ann Rheum Dis 2015;74(2):333-340. Curtis JR et al., Art Care Res 2012:64(12):1794-1803. Disclosure of Interest P. Taylor Consultant for: Pfizer, Eli Lilly & Company, M. Genovese Grant/research support from: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, Consultant for: Abbvie, Astellas, Eli Lilly & Company, Galapagos, Pfizer, Vertex, E. Keystone Grant/research support from: Abbott Laboratories, Amgen Inc., AstraZeneca Pharmaceuticals LP, Bristol-Meyers Squibb, F. Hoffman-La Roche Inc., Janssen Inc., Eli Lilly & Company, Novartis Pharmaceuticals, Pfizer Pharmaceuticals, Sanofi-Aventis, UCB, Consultant for: Abbott Laboratories, AstraZeneca Pharmaceuticals LP, Biotest, Bristol-Meyers Squibb, F. Hoffman-La Roche Inc., Genentech, Janssen Inc., Eli Lilly & Company, Merck, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories, Astrazeneca LP, Bristol-Meyers Squibb Canada, F. Hoffman-La Roche Inc., Janssen Inc., Pfizer Pharmaceuticals, UCB, Amgen, M. Weinblatt Grant/research support from: Bristol-Meyers Squibb, Crescendo Bioscience, UCB, Consultant for: Abbvie, Amgen, Astra Zeneca, Bristol-Meyers Squibb, Crescendo Bioscience, Eli Lilly & Company, Pfizer, Roche, UCB, J. Rancourt Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, E. Nantz Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, D. Schlichting Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, S. Zuckerman Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company, W. Macias Shareholder of: Eli Lilly & Company, Employee of: Eli Lilly & Company