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ObjectivesIxekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (IL-17A), has shown significant efficacy in the treatment of psoriatic arthritis (PsA) and sustained long-term clinical response without unexpected new safety outcome for an IL-17A inhibitor. Here, we report the updated safety profile of ixekizumab up to 3 years in patients with PsA.MethodsThis is an integrated safety analysis from four clinical trials in patients with PsA who received at least one dose of ixekizumab. Treatment-emergent adverse events (TEAEs) and selected adverse events (AEs) exposure-adjusted incidence rates (EAIRs) per 100 patient-years up to 3 years of exposure are reported.ResultsA total of 1401 patients with a cumulative ixekizumab exposure of 2247.7 patient-years were included in this analysis. The EAIR of patients with ≥1 TEAE was 50.3 per 100 patient-years and most TEAEs were mild to moderate in severity. Serious AEs were reported by 134 patients (EAIR=6.0). The most reported TEAEs were nasopharyngitis (EAIR=9.0) and upper respiratory tract infection (EAIR=8.3). Infections in general and injection site reactions were the most common TEAEs; the incidence rates of serious cases were low (EAIR ≤1.2). The EAIRs of malignancies (EAIR=0.7), inflammatory bowel disease (EAIR=0.1) including ulcerative colitis and Crohn’s disease, depression (EAIR=1.6), and major adverse cerebro-cardiovascular events (EAIR=0.5) were low. As assessed, based on year of exposure, incidence rates were decreasing or constant over time.ConclusionsIn this analysis, the overall safety profile and tolerability of ixekizumab are consistent with the known safety profile in patients with PsA. No new or unexpected safety events were detected.Trial registration numberNCT01695239,NCT02349295,NCT02584855,NCT03151551.

Background:Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets IL-17A, has shown improvements compared to placebo (PBO) not only in disease activity but also in various patient-reported outcomes (PROs) assessing physical function, quality of life (QoL), and work productivity in PsA patients treated for 24 weeks and sustained up to 52 weeks.1, 2Objectives:To report the effects of treatment with IXE on these PROs after up to 3 years of treatment.Methods:In SPIRIT-P2 (NCT02349295), a Phase 3 trial, 363 adult patients with active PsA and prior inadequate response or intolerance to 1 or 2 TNF inhibitors (TNFis) were randomized 1:1:1 to IXE 80 mg every 4 weeks (IXEQ4W; N=122) or every 2 weeks (IXEQ2W; N=123), or PBO (N=118) in the double-blind treatment period (Weeks 0-24). Both IXE regimens had a starting dose of 160 mg. Results are reported from a subset of the intent-to-treat population who were randomized to IXE at baseline (Week 0). The following PROs were assessed during Weeks 0-156: HAQ-DI (minimally clinically important difference [MCID] an improvement ≥0.35), medical outcomes survey Short Form-36 (SF-36) Physical and Mental Component Summary (PCS and MCS), European Quality of Life 5 Dimensions Visual Analog Scale (EQ-5D VAS), and Work Productivity and Activity Impairment Questionnaire-Specific Health Problem (WPAI-SHP; absenteeism, presenteeism, work productivity, and activity impairment). Missing values were imputed by observed analysis and modified baseline observation carried forward (mBOCF) for continuous data or by modified non-responder imputation (mNRI) for categorical data.Results:Mean baseline scores for SF-36 (PCS and MCS), EQ-5D VAS, and WPAI-SHP (Figure 1) and HAQ-DI (mean [SD]: IXEQ4W=1.2 [0.6]; IXEQ2W=1.2 [0.6]), indicated impaired physical function and QoL. The percentage of patients of who completed 156 weeks of the study in IXEQ4W and IXEQ2W arms were 57.4% (n=70) and 44.7% (n=55), respectively. Patients receiving IXE treatment up to 3 years reported sustained improvements in SF-36 (PCS and MCS), EQ-5D VAS, and WPAI-SHP (presenteeism, work productivity, and activity impairment) (Figure 1). Observed HAQ-DI mean change from baseline in IXEQ4W: -0.46 (0.62) and IXEQ2W: -0.48 (0.55). The percentage of IXE treated patients achieving MCID for HAQ-DI (improvement ≥0.35) was sustained at 3 years (Figure 2).Figure 1.Summary of Patient-Reported Outcomes presented as change from baseline at Week 156 (Observed and mBOCF): Intent-to-Treat Population (Patients Randomized to IXE at Baseline)Figure 2.Patients achieving HAQ-DI MCID Response up to Week 156 (Observed) and at Week 156 (mNRI) among patients with HAQ-DI≥0.35 at baseline: Intent-to-Treat Population (Patients Randomized to IXE at Baseline)Conclusion:Improvements in PROs, measuring physical and mental function, quality of life, and work productivity are maintained up to 3 years with IXE treatment in patients with active PsA who have had an inadequate response or intolerance to 1 or 2 TNFis.References:[1]Nash P, et al. Lancet. 2017;389(10086):2317-2327.[2]Genovese MC, et al. Rheumatology (Oxford). 2018;57(11):2001-2011.Disclosure of Interests:Ana-Maria Orbai Grant/research support from: Abbvie, Eli Lilly and Company, Celgene, Novartis, Janssen, Horizon, Consultant of: Eli Lilly; Janssen; Novartis; Pfizer; UCB. Ana-Maria Orbai was a private consultant or advisor for Sun Pharmaceutical Industries, Inc, not in her capacity as a Johns Hopkins faculty member and was not compensated for this service., Jordi Gratacos-Masmitja Grant/research support from: a grant from Pfizzer to study implementation of multidisciplinary units to manage PSA in SPAIN, Consultant of: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Speakers bureau: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Eva Dokoupilova Grant/research support from: Eli Lilly and Abbvie, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Arnaud Constantin Grant/research support from: Study was sponsored by Sanofi Genzyme, Consultant of: Consulting fees from Abbvie, BMS, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, UCB, Amanda M. Gellett Shareholder of: Eli Lilly and company, Employee of: Eli Lilly and company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Julie Birt Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Vladimir Geneus Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB

Background:Ixekizumab (IXE), a high-affinity monoclonal antibody selectively targeting IL-17A, was superior to adalimumab (ADA) at Week (Wk) 24 for simultaneous achievement of ACR50 and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100) (primary endpoint) in patients (pts) with active PsA from SPIRIT-H2H1. SPIRIT-H2H had two major secondary endpoints and achieved both: noninferiority of IXE to ADA for ACR50 at Wk 24, and superiority of IXE to ADA for PASI 100 at Wk 24.Objectives:To determine how concomitant conventional synthetic DMARD (csDMARD) use affects safety and efficacy of IXE and ADA in prespecified subgroups defined by biologic monotherapy, concomitant MTX use, and concomitant csDMARD use through Wk 52 in SPIRIT-H2H.Methods:SPIRIT-H2H (NCT03151551) was a 52-week, multicentre, randomised, open-label, assessor-blinded, parallel-group study evaluating the efficacy and safety of IXE versus ADA in adults with PsA and naïve to biologic DMARDs. Patients were required to have active PsA fulfilling Classification for Psoriatic Arthritis (CASPAR) criteria and ≥3/68 tender and ≥3/66 swollen joints, ≥3% plaque psoriasis BSA involvement, no prior treatment with bDMARDs, and with prior inadequate response to ≥1 csDMARD (but not necessarily current treatment with csDMARDs). Randomization (1:1) was stratified by concomitant use of csDMARD and the presence/absence of moderate to severe PsO (baseline: BSA≥10% + PASI≥12, + static Physician’s Global Assessment≥3). Patients (N=566) received IXE/ADA through 52 wks according to the labelled dose dependent on presence/absence of moderate-to-severe PsO. In this prespecified subgroup analysis by presence or absence of csDMARDs, efficacy outcomes through wk 52 were compared between IXE and ADA using logistic regression models and Fisher’s exact tests. Missing data were imputed using non-responder imputation.Results:At baseline, 167 of 283 IXE-treated patients and 169 of 283 ADA-treated patients had concomitant MTX use. Of these, 9.0% (15/167) and 7.1% (12/169) treated with IXE and ADA, respectively, were taking an additional csDMARD (sulfasalazine, cyclosporine, or leflunomide). A significantly greater proportion of patients on IXE versus ADA achieved the primary endpoint or PASI 100 when used as monotherapy or in combination with csDMARD (Figure 1A and 1C). At Wk 52, the proportion of patients achieving ACR50 was not statistically different between IXE and ADA, regardless of monotherapy or concomitant csDMARD use (Figure 1B). A significantly higher proportion of patients achieved MDA on IXE compared to ADA in the monotherapy subgroup (49% vs 33%), while the response rates were similar in both combination subgroups (Figure 1D). These data support consistent ACR50, PASI 100, and MDA response for IXE across all three subgroups. Frequencies of adverse events were similar across the three subgroups for IXE and ADA (Figure 2).Conclusion:As with prior studies,2,3consistent efficacy across multiple PsA disease-specific endpoints was observed with IXE in SPIRIT-H2H, regardless of whether IXE was taken as monotherapy or in combination with MTX or another csDMARD. No unexpected safety signals were found for either agent.References:[1]Mease et al, Ann Rheum Dis 2020;79:123-31.[2]Coates et al, RMD Open 2017;3:e000567.[3]Nash et al, RMD Open 2018;4:e000692.Disclosure of Interests:Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Anthony Sebba Consultant of: Genentech, Gilead, Lilly, Regeneron Pharmaceuticals Inc., Sanofi, Speakers bureau: Lilly, Roche, Sanofi, Eric Ruderman Consultant of: Pfizer, Amanda Gellett Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Christophe Sapin Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Soyi Liu Leage Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Sreekumar Pillai Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Paulo Reis Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB

Background:Patients with psoriatic arthritis (PsA) require long-term treatment, which may lead to adverse events (AEs). Ixekizumab, an interleukin-17A antagonist, is approved for the treatment of adults with active PsA.Objectives:We report a summary of safety outcomes for patients enrolled in 4 PsA studies with up to 3 years of exposure to ixekizumab.Methods:This integrated safety analysis included all patients with PsA who received at least 1 dose of ixekizumab (80 mg every 2 or 4 weeks) in 4 clinical trials (NCT01695239, NCT02349295, NCT02584855, NCT03151551). Safety outcomes included treatment-emergent adverse events (TEAEs), serious AEs (SAEs), discontinuations due to AEs, deaths, and AEs of special interest.Results:A total of 1401 patients were included in this safety analysis (51.5% female; mean age 49 years), with 2247.6 patient-years of exposure (Table 1). In all, 1131 patients (80.7%) reported ≥1 TEAE (exposure-adjusted incidence rate per 100 patient-years [IR] 50.3, 95% CI 47.5–53.3), mostly mild (32.9%) or moderate (39.7%) in severity. The most common TEAEs were nasopharyngitis (n=202, IR 9.0), upper respiratory infections (n=186, IR 8.3), and injection site reaction (n=156, IR 6.9). SAEs were reported by 134 patients (IR 6.0, 95% CI 5.0–7.1). 115 (8.2%) patients discontinued due to AEs (IR 5.1, 95% CI 4.3–6.1). Six deaths were reported (IR 0.3, 95% CI 0.1–0.6). Allergic reactions/hypersensitivity were reported in 102 patients (IR 4.5, 95% CI 3.7–5.5). Three cases were adjudicated as de novo inflammatory bowel disease (IR 0.13, 95% CI 0.04–0.41); 1 was ulcerative colitis (IR 0.04, 95% CI 0.01–0.32), 2 were Crohn’s disease (IR 0.09, 95% CI 0.02–0.36). Major adverse cardiac events occurred in 12 patients (IR 0.5) and malignancies in 15 (IR 0.7), 9 of which were non-melanoma skin cancer. Opportunistic infections occurred in 40 (2.9%) patients (IR 1.8, 95% CI 1.3–2.4). Candidiasis occurred in 24 patients (oral: IR 0.7, 95% CI 0.4–1.2; oral fungal infection: IR 0.3, 95% CI 0.1–0.6; esophageal infection: IR 0.1, 95% CI 0.0–0.4). No active or reactive cases of tuberculosis were reported. Other opportunistic infections included hepatitis B (IR 0.0, 95% CI 0.0–0.3), herpes simplex (IR 1.8, 95% CI 1.3–2.5), and herpes zoster (IR 0.7, 95% CI 0.4–1.2).Conclusion:The safety profile of ixekizumab across 4 clinical trials and up to 3 years of continuous treatment in patients with active PsA was consistent with the known safety profile reported in previous studies for psoriasis and PsA. No new safety events were found in this analysis.Pooled Ixekizumab(N=1401; Total Patient-Years=2247.6)n (IR)95% CIYear 0–1(n=1401)n (IR)95% CIYear 1–2(n=946)n (IR)95% CIYear 2–3(n=510)n (IR)95% CIYear ≥3(n=89)n (IR)95% CITotal Patient-Years2247.71207.3689.8347.72.9Patients with ≥1 TEAE1131 (50.3)1050 (87.0)496 (71.9)234 (67.3)6 (206.2)47.5–53.381.9–92.465.9–78.559.2–76.592.6–458.9SAEs134 (6.0)72 (6.0)53 (7.7)19 (5.5)1 (34.4)5.0–7.14.7–7.55.9–10.13.5–8.64.8–243.9Discontinuations due to AEs115 (5.1)61 (5.1)37 (5.4)17 (4.9)0 (0)4.3–6.13.9–6.53.9–7.43.0–7.90.0–274.7Hepatic reactions112 (5.0)80 (6.6)32 (4.6)14 (4.0)0 (0)4.1–6.05.3–8.33.3–6.62.4–6.80.0–274.7Allergic reaction/hypersensitivity102 (4.5)83 (6.9)23 (3.3)5 (1.4)0 (0)3.7–5.55.5–8.52.2–5.00.6–3.50.0–274.7Serious infection28 (1.2)18 (1.5)9 (1.3)3 (0.9)0 (0)0.9–1.80.9–2.40.7–2.50.3–2.70.0–274.7Malignancies15 (0.7)4 (0.3)8 (1.2)4 (1.2)0 (0)0.4–1.10.1–0.90.6–2.30.4–3.10.0–274.7Major adverse cardiac events12 (0.5)3 (0.2)8 (1.2)1 (0.3)0 (0)0.3–0.90.1–0.80.6–2.30.0–2.00.0–274.7Inflammatory bowel disease3 (0.1)3 (0.2)1 (0.1)0 (0.0)0 (0.0)0.0–0.40.1–0.80.0–1.00.0–2.30.0–274.7 Ulcerative colitis1 (0.0)1 (0.1)1 (0.1)0 (0.0)0 (0.0)0.0–0.30.0–0.60.0–1.00.0–2.30.0–274.7 Crohn’s disease2 (0.1)2 (0.2)0 (0.0)0 (0.0)0 (0.0)0.0–0.40.0–0.70.0–1.20.0–2.30.0–274.7AE, adverse event; CI, confidence interval; IR, exposure-adjusted incidence rate per 100 patient-years; SAE, serious adverse event; TEAE, treatment-emergent adverse event.Disclosure of Interests:Carlos Sesin Speakers bureau: Amgen, AbbVie, Sanofi, Radius, Pfizer, Eli Lilly and Company, Novartis, Gaia Gallo Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Amanda Gellett Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Andris Kronbergs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Wen Xu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Himanshu Patel Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Atul Deodhar Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Glaxo Smith & Kline, Janssen, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Eli Lilly and Company, Glaxo Smith & Kline, Novartis, Pfizer, UCB, Bernard Combe Speakers bureau: AbbVie, BMS, Gilead-Galapagos, Eli Lilly and Company, MSD, Pfizer, Roche Chugai, Consultant of: AbbVie, Bayer, Gilead-Galapagos, Janssen, Eli Lilly and Company, Novartis, Roche Chugai, Grant/research support from: AbbVie, Eli Lilly and Company, Pfizer, Roche Chugai, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Janssen, Novartis, Eli Lilly and Company, MSD, Pfizer, Consultant of: AbbVie, Janssen, Novartis, Eli Lilly and Company, MSD, Pfizer.

Background:Ixekizumab (IXE) is a high affinity monoclonal antibody that selectively targets interleukin-17A. In the SPIRIT-P2 study, IXE every 4 (Q4W) or 2 (Q2W) weeks was superior to placebo (PBO) in improving the signs and symptoms of psoriatic arthritis (PsA) at Week 24 in patients (pts) with prior inadequate response or intolerance to 1 or 2 tumor necrosis factor inhibitors (TNFi).Objectives:To determine efficacy and safety of IXE treatment up to 3 years in pts with PsA.Methods:In SPIRIT-P2 (NCT02349295), 310 pts entered the extension period where pts maintained their original ixekizumab dose, and placebo pts received IXEQ4W or IXEQ2W (1:1). Pts failing to demonstrate ≥20% improvement in both tender and swollen joint counts at Week 32, or any subsequent visit, were discontinued (mandatory discontinuation criteria). Efficacy outcomes were ACR20/50/70 response, Psoriasis Area and Severity Index (PASI) 75/90/100 response, Leeds Enthesitis Index (LEI), Leeds Dactylitis Index-Basic (LDI-B), Minimal Disease Activity (MDA), and Disease Activity in Psoriatic Arthritis (DAPSA). Ad-hoc efficacy data are presented for intent-to-treat (ITT) pts initially randomized to IXE at Week 0. Observed and modified non-responder imputation (mNRI; missing data treated as non-response for pts discontinued due to lack of efficacy or adverse events [AEs]) was applied to categorical measures. Observed and modified baseline observation carried forward (mBOCF) was applied to continuous efficacy measures. Safety was analysed in pts exposed to at least one dose of IXE.Results:Of the 245 pts initially randomized to IXE at Week 0 (ITT), 64 (26.1%) pts discontinued due to lack of efficacy and 22 (9.0%) pts due to mandatory discontinuation criteria. Efficacy results are summarized below (Figure 1). Pts in SPIRIT-P2 who received IXEQ4W and IXEQ2W for 156 weeks reported sustained improvement in ACR responses and manifestations of PsA, including enthesitis, dactylitis, and skin outcomes. Treat-to-target measures such as MDA and DAPSA (Low Disease Activity or Remission) were achieved by 30.8% and 47.7% of pts, respectively on IXEQ4W, and by 29.2% and 40.7% of pts, respectively on IXEQ2W. Incidence rates (IR) of treatment-emergent adverse events (TEAEs) are provided below (Figure 2). Most TEAEs were mild or moderate in severity, and 38 out of 337 (5.9%) pts (safety population) discontinued due to AEs. The most common TEAEs were infections (IR=33.1) and injection site reactions (IR=5.4). Three deaths were reported in the study.Figure 1.Efficacy Outcome Measures at Week 156 (Intent-to-treat Population).ACR=American College of Rheumatology; IXE=ixekizumab; LEI=Leeds Enthesitis Index; LDI-B=Leeds Dactylitis Index-Basic; mNRI=modified non-responder imputation; PASI=Psoriasis Area and Severity Index; Q2W=every two weeks; Q4W=every four weeks.Figure 2.Safety Outcome Measures (Weeks 0-156).Safety was analysed in patients exposed to at least one dose of ixekizumab. During the double-blind treatment period (Weeks 0-24), one patient reported serious adverse events of anal fistula and anal abscess, which were considered by the sponsor to be IBD; however, an independent adjudication committee of external experts reviewed the case and determined the events to be “Not IBD.”Conclusion:In pts treated with IXE who had prior inadequate response or intolerance to 1 or 2 TNFi, improvements in the signs and symptoms of PsA persisted up to 3 years. No unexpected safety signals were observed, and the safety profile was consistent with previous studies of IXE.Disclosure of Interests:Jordi Gratacos-Masmitja Grant/research support from: a grant from Pfizzer to study implementation of multidisciplinary units to manage PSA in SPAIN, Consultant of: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Speakers bureau: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Anthony Turkiewicz Grant/research support from: Received research grants from AbbVie, Eli Lilly and Company, Janssen, Novartis, and Pfizer, Consultant of: Received consulting fees from AbbVie, Eli Lilly and Company, Janssen, Novartis, and Pfizer, Speakers bureau: On speaker bureau for Abbvie, Eli Lilly and Company, Janssen, Novartis, Pfizer, Eva Dokoupilova Grant/research support from: Eli Lilly, AbbVie, Novartis, Amanda M. Gellett Shareholder of: Eli Lilly and company, Employee of: Eli Lilly and company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Vladimir J. Geneus Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Arnaud Constantin Grant/research support from: Study was sponsored by Sanofi Genzyme, Consultant of: Consulting fees from Abbvie, BMS, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, UCB