Efficacy and Safety of Sarilumab in Combination With csdmards in Patients With Active Rheumatoid Arthritis Who Were Inadequate Responders or Intolerant of Anti-TNF Therapy: Results From a Phase 3 Study Roy Fleischmann, 1 Geraldo da Rocha Castelar-Pinheiro, 2 Jan Brzezicki, 3 Pawel Hrycaj, 4 Yong Lin, 5 Janet van Adelsberg, 6 Neil M.H. Graham, 6 Hubert van Hoogstraten, 5 Deborah Bauer, 5 Gerd R. Burmester 7 1 Metroplex Clinical Research Center, Dallas, TX, USA; 2 Discipline of Rheumatology, Rio de Janeiro State University, Rio de Janeiro, Brazil; 3 Centrum Kliniczno-Badawcze, Elblag, Poland; 4 Department of Rheumatology and Clinical Immunology, Poznań University of Medical Sciences, Poznań, Poland; 5 Sanofi, Bridgewater, NJ, USA; 6 Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 7 Department of Rheumatology and Clinical Immunology, Charité University Medicine, Berlin, Germany TARGET Clinical Trial Identifier: NCT01709578
Disclosures Roy Fleischmann has received research grants from AbbVie, Amgen, Ardea, AstraZeneca, BMS, Celgene, GSK, Janssen, Eli Lilly, Merck, Pfizer, Roche, Sanofi Aventis, and UCB; and has received consulting fees from AbbVie, Akros, Amgen, AstraZeneca, BMS, Janssen, Eli Lilly, Pfizer, Roche, and UCB Geraldo da Rocha Castelar-Pinheiro has received consulting fees from AbbVie, AstraZeneca, GSK, Hospira, Janssen, Pfizer, Roche, RuiYi, and Sanofi Jan Brzezicki and Pawel Hrycaj have nothing to disclose Yong Lin is an employee of Sanofi and may hold stock and/or stock options in the company Janet van Adelsberg and Neil M.H. Graham are employees of Regeneron Pharmaceuticals, Inc, and may hold stock and/or stock options in the company Hubert van Hoogstraten and Deborah Bauer are employees of Sanofi and may hold stock and/or stock options in the company Gerd R. Burmester has received research grants from AbbVie, Pfizer, UCB, and Roche; has received consulting fees from AbbVie, BMS, Pfizer, Merck, MedImmune, UCB, and Roche; and has served on speakers bureaus for AbbVie, BMS, Pfizer, Merck, UCB, and Roche This study was sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. Presentation development support was provided by Kristi Porter, PhD, MedThink SciCom, and funded by Sanofi and Regeneron Pharmaceuticals, Inc 2
Background Sarilumab is an investigational human monoclonal antibody directed against the interleukin 6 receptor Sarilumab + MTX has previously demonstrated efficacy and safety in patients with active, moderate-to-severe RA 1 The TARGET study (NCT01709578) evaluated the efficacy and safety of sarilumab + csdmards in adults with active, moderate-to-severe RA with inadequate response to or intolerance of 1 TNF inhibitor(s) csdmard, conventional synthetic disease-modifying antirheumatic drug; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumor necrosis factor. 1. Genovese et al. Arthritis Rheumatol. 2015;67:1424-1437. 3
TARGET Study Design 12 weeks (rescue a ) 24 weeks N=546 randomized Sarilumab 200 mg q2w + csdmards (n=184) Inadequate response or intolerance to anti-tnf R Sarilumab 150 mg q2w + csdmards Placebo q2w + csdmards 1 EP HAQ-DI 1 EP ACR20 EXTEND a Patients with <20% improvement from baseline in either SJC or TJC for 2 consecutive assessments were eligible for rescue at week 12 with open-label sarilumab 200 mg q2w in the long-term safety study EXTEND. csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. csdmard, conventional synthetic disease-modifying antirheumatic drug; EP, endpoint; HAQ-DI, Health Assessment Questionnaire Disability Index; q2w, every 2 weeks; SJC, swollen joint count; TJC, tender joint count; TNF, tumor necrosis factor. 4
TARGET Inclusion and Exclusion Criteria Inclusion criteria DX of RA 6 months by ACR/EULAR criteria Prior anti-tnf therapy failure and/or intolerance to 1 anti-tnf drug (defined by the investigator) Active disease, defined as 6 of 66 swollen joints and 8 of 68 tender joints hs-crp 8 mg/l at screening Continuous treatment for 12 weeks before BL with 1 csdmards (stable dose for 6 weeks before screening) MTX: 10-25 mg/week or per local labeling requirements, if the dose range differs Leflunomide: 10-20 mg daily Sulfasalazine: 1000-3000 mg daily Hydroxychloroquine: 200-400 mg daily Key exclusion criteria Rx with anti-tnf agents within ~5 half-lives Prior treatment with any cell-depleting agents unless normal lymphocyte and CD 19+ lymphocyte count Prior treatment with anti IL-6 or anti IL-6 receptor antagonist therapies Oral glucocorticoid > prednisone 10 mg per day or equivalent per day, or a change in dosage within 4 weeks before randomization Any parenteral or intra-articular glucocorticoid injection within 4 weeks before baseline Active infection BL, baseline; csdmard, conventional synthetic disease-modifying antirheumatic drug; EULAR, European League Against Rheumatism; hs-crp, high-sensitivity C-reactive protein; IL-6, interleukin 6; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumor necrosis factor. 5
TARGET: Primary and Main Secondary Efficacy Endpoints Coprimary efficacy endpoints ACR20 response at week 24 Change from baseline in HAQ-DI at week 12 Secondary efficacy endpoints Change from baseline in DAS28-CRP at week 24 ACR50/70 at week 24 DAS28-CRP <2.6 at week 24 Change from baseline in CDAI at week 24 Change from baseline in HAQ-DI at week 24 Other secondary endpoints SF-36 at week 24; FACIT Fatigue at week 24; Morning stiffness at week 24; WPS-RA at week 24; RAID at week 24; EQ-5D-3L at week 24 CDAI, clinical disease activity index; DAS28-CRP, disease activity score in 28 joints using C-reactive protein; FACIT, Functional Assessment of Chronic Illness Therapy; HAQ-DI, Health Assessment Questionnaire Disability Index; RAID, Rheumatoid Arthritis Impact of Disease; SF-36, Short-Form-36; WPS-RA, Work Productivity Survey Rheumatoid Arthritis. 6
Baseline Demographics and Disease Activity Placebo + csdmard Sarilumab 150 mg q2w + csdmard Sarilumab 200 mg q2w + csdmard (n=184) Age, mean, y 51.9 54.0 52.9 Female, % 85.1 78.5 82.1 Caucasian, % 68.5 74.0 70.7 Region, % Region 1 42.5 42.5 42.9 Region 2 40.9 40.9 40.2 Region 3 16.6 16.6 16.8 RA duration, mean, y 12.0 11.6 12.7 >1 prior anti-tnfs, % 25.4 20.6 23.5 RF positive, % 78.9 74.6 72.9 Anti-CCP antibody positive, % 83.3 75.0 76.1 Tender joint count (68 assessed), mean 29.4 27.7 29.6 Swollen joint count (66 assessed), mean 20.2 19.6 20.0 CRP, mean, mg/l 26.0 23.6 30.8 HAQ-DI (0-3), mean 1.8 1.7 1.8 DAS28-CRP, mean 6.2 6.1 6.3 CCP, citrullinated peptide antibody; CRP, C-reactive protein; csdmard, conventional synthetic disease-modifying antirheumatic drug; DAS28-CRP, disease activity score in 28 joints using CRP; HAQ-DI, Health Assessment Questionnaire Disability Index; q2w, every 2 weeks; RA, rheumatoid arthritis; RF, rheumatoid factor; TNF, tumor necrosis factor. Region 1: Australia, Canada, Czech Republic, Germany, Greece, Hungary, Israel, Italy, New Zealand, Portugal, Spain, United States. Region 2: Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, Mexico, Peru. Region 3: Lithuania, Poland, Russia, South Korea, Taiwan, Thailand, Turkey, Ukraine. 7
TARGET Patient Disposition Screened (n=1224) Randomized (n=546) Placebo n=181 patients Sarilumab 150 mg q2w n=181 patients Sarilumab 200 mg q2w n=184 patients 17 discontinued - 9 AE - 5 lack of efficacy - 1 poor compliance - 2 other reasons 31 discontinued - 18 AE - 4 lack of efficacy - 2 poor compliance - 7 other reasons 25 discontinued - 17 AE - 2 lack of efficacy - 1 poor compliance - 5 other reasons 63 rescued 25 rescued 26 rescued 101 patients completed the study - 94 rolled over to EXTEND 125 patients completed the study - 121 rolled over to EXTEND 133 patients completed the study - 127 rolled over to EXTEND Efficacy population included the intent-to-treat population, which consisted of all randomized patients. Safety population included all randomized patients who received 1 dose of the study medication. AE, adverse event; q2w, every 2 weeks. 8
ACR response, % ACR response, % ACR response, % ACR20/50/70 Responses at Week 24 100 ACR20 Primary EP 100 ACR50 100 ACR70 90 90 90 80 80 80 70 60 50 40 30 20 10 0 33.7 * * 55.8 60.9 70 60 50 40 30 20 10 0 18.2 * * 37.0 40.8 70 60 50 40 30 20 10 0 7.2 19.9 16.3 *P<0.0001. P=0.0002. P=0.0056 vs placebo + csdmard. Placebo + csdmard Sarilumab 150 mg q2w + csdmard Sarilumab 200 mg q2w + csdmard (n=184) csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. Data analyzed by and evaluated using the 2-sided Cochran-Mantel-Haenszel test stratified by prior biologic use and region. Patients are considered nonresponders from the time they started rescue medication or discontinued study medication. csdmard, conventional synthetic diseasemodifying antirheumatic drug; q2w, every 2 wks. 9
Mean change from baseline Improvement in HAQ-DI Scores at Week 12 0-0.2-0.4-0.6-0.3-0.5-0.5 * Placebo + csdmard Sarilumab 150 mg q2w + csdmard Sarilumab 200 mg q2w + csdmard (n=184) -0.8-1 *P=0.0007. P=0.0004 vs placebo + csdmard. csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. Data analyzed using a mixed model for repeated measures, which includes baseline, treatment, number of previous anti-tnfs, region, visit, and treatment-by-visit interaction. csdmard, conventional synthetic disease-modifying antirheumatic drug; HAQ-DI, Health Assessment Questionnaire Disability Index; q2w, every 2 weeks. 10
Change from baseline, mean Proportion of patients, % Change from baseline, mean Change from baseline, mean TARGET Selected Secondary Endpoints: CDAI, DAS28-CRP, HAQ-DI From Baseline to Week 24 0-5 BL 2 4 8 12 16 20 24 CDAI 0-0.5 BL 2 4 8 12 16 20 24 DAS28- CRP -10-15 -20-25 -30-35 n=172 n=164 n=170 n=100 n=127 n=136-1 -1.5-2 -2.5-3 -3.5 n=168 n=163 n=169 n=99 n=126 n=136 0-0.1-0.2-0.3-0.4-0.5-0.6-0.7-0.8 BL 2 4 8 12 16 20 24 HAQ-DI n=170 n=165 n=171 n=101 n=127 n=136 DAS28-CRP <2.6 and 2.6 DAS28-CRP 3.2 7.2 24.9 28.8 CDAI, clinical disease activity index; DAS28-CRP, disease activity score in 28 joints using C-reactive protein; HAQ-DI, Health Assessment Questionnaire Disability Index; q2w, every 2 weeks. 45 40 35 30 25 20 15 10 5 0 6.6 7.7 11.4 2.6 DAS28-CRP 3.2 DAS28-CRP <2.6 11
Overview of Safety Patients, n (%) Placebo + csdmard Sarilumab + csdmard 150 mg q2w 200 mg q2w (n=184) TEAE 90 (49.7) 119 (65.7) 120 (65.2) Treatment-emergent SAE, n (%) 6 (3.3) 6 (3.3) 10 (5.4) SIE, n (%) 2 (1.1) 1 (0.6) 2 (1.1) TEAE leading to death, n (%) 1 (0.6) a 0 0 Treatment discontinuation due to TEAE, n (%) 8 (4.4) 14 (7.7) 17 (9.2) csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. csdmard, conventional synthetic disease-modifying antirheumatic drug; q2w, every 2 weeks; SAE; serious adverse event; SIE, serious infectious event; TEAE, treatment-emergent adverse event. n (%) is the number and percentage of patients with at least 1 TEAE. a One death in the placebo group was a result of a motor vehicle accident. 12
Most Frequently Reported TEAEs ( 5%) Frequent TEAEs by SOC, n (%) Placebo + csdmard Sarilumab + csdmard 150 mg q2w 200 mg q2w (n=184) All TEAEs 90 (49.7) 119 (65.7) 120 (65.2) Infections and infestations 48 (26.5) 40 (22.1) 56 (30.4) Urinary tract infection 12 (6.6) 6 (3.3) 13 (7.1) Nasopharyngitis 9 (5.0) 11 (6.1) 7 (3.8) Blood and lymphatic system disorders 9 (5.0) 25 (13.8) 29 (15.8) Neutropenia 2 (1.1) 23 (12.7) 23 (12.5) Metabolism and nutrition disorders 7 (3.9) 21 (11.6) 15 (8.2) Hypertriglyceridemia 3 (1.7) 11 (6.1) 5 (2.7) Administration site conditions 10 (5.5) 24 (13.3) 22 (12.0) Injection site erythema 0 11 (6.1) 7 (3.8) Investigations 8 (4.4) 19 (10.5) 30 (16.3) ALT increased 2 (1.1) 5 (2.8) 10 (5.4) csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. ALT, alanine aminotransferase; csdmard, conventional synthetic disease-modifying antirheumatic drug; q2w, every 2 weeks; SOC, system organ class. TEAE: treatment-emergent adverse event reported by investigators. 13
Laboratory Abnormalities Through Week 24 Patients, n (%) Absolute neutrophil count Placebo + csdmard Sarilumab + csdmard 150 mg q2w 200 mg q2w (n=184) 0.5 to 1.0 Giga/L (grade 3) 1 (0.6) 10 (5.5) 16 (8.7) <0.5 Giga/L (grade 4) 0 4 (2.2) 2 (1.1) Alanine aminotransferase >ULN to 3 ULN 46 (25.4) 76 (42.0) 80 (43.5) >3 ULN to 5 ULN 2 (1.1) 4 (2.2) 7 (3.8) >5 ULN 0 0 1 Platelet count 50 to 100 Giga/L 0 0 5 (2.7) <50 Giga/L 0 0 1 (0.5) csdmard, conventional synthetic disease-modifying antirheumatic drug; HDL, high-density lipoprotein; LDL, low-density lipoprotein; q2w, every 2 weeks; ULN, upper limit of normal. 14
Improvements in Laboratory Parameters at Week 24 Sarilumab + csdmard Laboratory parameters Placebo + csdmard 150 mg q2w 200 mg q2w (n=184) Hemoglobin, mean change from BL, g/l -0.27 8.03 9.00 Patients with AE of anemia, n (%) 5 (2.8) 0 1 (0.5) CRP, mean change from BL, mg/l -5.21-13.11-29.06 Albumin, mean change from BL, g/l 0.87 3.27 4.40 csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. AE, adverse event; BL, baseline; CRP, C-reactive protein; csdmard, conventional synthetic disease-modifying antirheumatic drug; q2w, every 2 weeks. 15
Conclusions Sarilumab 150 and 200 mg q2w + csdmard demonstrated clinical efficacy and improvement in physical function versus placebo + csdmard in patients with active RA who were inadequate responders to or intolerant of anti-tnfs TEAEs leading to treatment discontinuation and SAEs (200 mg only) were more frequent in the sarilumab-treated groups compared with placebo each with concomitant csdmard Serious infections were infrequent, and the incidence was similar between sarilumab-treated and placebo groups Adverse events and laboratory changes were consistent with IL-6 blockade and observations from the MOBILITY study Neutropenia was among the most frequent TEAEs in the sarilumab + csdmard treatment groups csdmard, conventional synthetic disease-modifying antirheumatic drug; IL-6, interleukin 6; q2w, every 2 weeks; RA, rheumatoid arthritis; SAE, serious adverse event; TEAE, treatment-emergent adverse event; TNF, tumor necrosis factor. 16
Acknowledgments The authors would like to thank the patients and investigators whose participation and contributions made this study possible The authors acknowledge Kristi Porter, PhD (MedThink SciCom), whose work was funded by Sanofi and Regeneron Pharmaceuticals, Inc, for medical writing assistance with this presentation 17
Backup Slides 18
Mean change from baseline Mean change from baseline HAQ-DI at Week 12 0 ITT population (n=546) 0 By geographic region Region 1 (n=208) Region 2 (n=209) Region 3 (n=89) -0.1-0.2-0.3-0.2-0.3-0.13-0.14-0.25-0.4-0.6-0.5-0.5-0.4-0.5-0.6-0.36-0.39-0.52-0.38-0.8-0.7-0.8-0.67-0.7-1 *P=0.0007. **P=0.0004 vs placebo + csdmards Placebo + csdmard Region 2 had a placebo response greater than the mcid at week 12, but the treatment benefit with sarilumab was consistent across all regions -0.9-1 Sarilumab 150 mg q2w + csdmard P value for interaction = 0.9407. Sarilumab 200 mg q2w + csdmard (n=184) Change from baseline in HAQ-DI at week 12 was analyzed using a mixed model for repeated measures adjusted for prior biologic use, region, and baseline HAQ-DI score as covariate. csdmard, non-biologic disease-modifying antirheumatic drug; HAQ-DI, Health Assessment Questionnaire Disability Index; ITT, intent-to-treat; mcid, minimally clinically important difference; q2w, every 2 weeks. 19
HAQ-DI response, % HAQ-DI response, % HAQ-DI Responders at Week 24 100 90 80 70 60 50 40 30 20 10 0 HAQ-DI improvement 0.22 35.4 * 47.5 56.0 *P=0.0137. P<0.0001 vs placebo + csdmard 100 90 80 70 60 50 40 30 20 10 0 31.5 HAQ-DI improvement 0.30 * 43.1 47.3 *P=0.0165. P=0.0014 vs placebo + csdmard Placebo + csdmard Sarilumab 150 mg q2w + csdmard Sarilumab 200 mg q2w + csdmard (n=184) csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. csdmard, conventional synthetic disease-modifying antirheumatic drug; HAQ-DI, Health Assessment Questionnaire Disability Index; q2w, every 2 weeks. 20
Number (%) of Patients With TEAEs of Special Interest a Placebo + Sarilumab + csdmard TEAEs of special interest (MedDRA PT level), n (%) csdmard 150 mg q2w 200 mg q2w (n=184) Infections 48 (26.5) 40 (22.1) 56 (30.4) Serious infections 2 (1.1) 1 (0.6) 2 (1.1) Herpes Zoster 1 (0.6) 0 2 (1.1) Tuberculosis 0 0 0 Leukopenia 3 (1.7) 26 (14.4) 26 (14.1) Thrombocytopenia 0 1 (0.6) 5 (2.7) Hepatic disorders b 4 (2.2) 8 (4.4) 19 (10.3) Diverticulitis/Potential GI perforations 0 0 0 GI ulcerations 0 1 (0.6) 0 Elevations in lipids 5 (2.8) 21 (11.6) 15 (8.2) Hypersensitivity 7 (3.9) 10 (5.5) 11 (6.0) Anaphylaxis 0 0 0 Injection site reactions 2 (1.1) 13 (7.2) 15 (8.2) Malignancy 1 (0.6) 1 (0.6) 1 (0.5) Malignancy excluding NMSC 1 (0.6) 1 (0.6) 0 Lupus-like syndrome 0 0 0 Demyelinating disorders 0 0 0 csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. csdmard, conventional synthetic disease-modifying antirheumatic drug; GI, gastrointestinal; MedDRA, Medical Dictionary of Regulatory Activities; NMSC, nonmetastatic squamous cell; PT, preferred term; q2w, every 2 weeks; TEAE, treatment-emergent adverse event. a TEAEs of special interest as reported by investigator. b Hepatic disorders were generally nonserious elevations in transaminases. 21
Serious Adverse Events by Primary System Organ Class and Preferred Term Safety Population (I) Placebo Sarilumab + csdmard Serious adverse events, n (%) a + csdmard (N=181) 150 mg q2w (N=181) 200 mg q2w (N=184) Any class 6 (3.3) 6 (3.3) 10 (5.4) Infections and infestations 2 (1.1) 1 (0.6) 2 (1.1) Cellulitis 1 (0.6) 1 (0.6) 1 (0.5) Pneumonia 0 0 1 (0.5) Bacteremia 1 (0.6) 0 0 Bronchitis 1 (0.6) 0 0 Osteomyelitis 0 1 (0.6) 0 Neoplasms benign, malignant and unspecified (including cysts and polyps) 1 (0.6) 0 0 Ureteric cancer 1 (0.6) 0 0 Blood and lymphatic system disorders 1 (0.6) 1 (0.6) 1 (0.5) Neutropenia 0 1 (0.6) 1 (0.5) Anemia 1 (0.6) 0 0 Nervous system disorders 0 1 (0.6) 1 (0.5) Ischemic stroke 0 0 1 (0.5) Syncope 0 1 (0.6) 0 Cardiac disorders 0 0 2 (1.1) Acute myocardial infarction 0 0 1 (0.5) Atrioventricular block second degree 0 0 1 (0.5) Endocarditis noninfective 0 0 1 (0.5) csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. csdmard, conventional synthetic disease-modifying antirheumatic drug; q2w, every 2 weeks. a SAEs, treatment-emergent serious adverse events as reported by investigator. 22
Serious Adverse Events by Primary System Organ Class and Preferred Term Safety Population (II) Placebo Sarilumab + csdmard Serious adverse events, n (%) a + csdmard (N=181) 150 mg q2w (N=181) 200 mg q2w (N=184) Vascular disorders 0 0 1 (0.5) Venous thrombosis limb 0 0 1 (0.5) Respiratory, thoracic and mediastinal disorders 0 1 (0.6) 0 Pulmonary embolism 0 1 (0.6) 0 Gastrointestinal disorders 0 1 (0.6) 1 (0.5) Inguinal hernia 0 0 1 (0.5) Gastric ulcer hemorrhage 0 1 (0.6) 0 Hepatobiliary disorders 1 (0.6) 0 0 Mixed liver injury 1 (0.6) 0 0 Musculoskeletal and connective tissue disorders 1 (0.6) 1 (0.6) 1 (0.5) Intervertebral disc disorder 0 0 1 (0.5) Intervertebral disc protrusion 0 1 (0.6) 0 Rheumatoid arthritis 1 (0.6) 0 0 Investigations 0 0 2 (1.1) Neutrophil count decreased 0 0 1 (0.5) Transaminases increased 0 0 1 (0.5) Injury, poisoning and procedural complications 2 (1.1) 0 1 (0.5) Post-procedural hemorrhage 0 0 1 (0.5) Ankle fracture 1 (0.6) 0 0 Road traffic accident 1 (0.6) 0 0 csdmards: methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine. csdmard, conventional synthetic disease-modifying antirheumatic drug; q2w, every 2 weeks. a SAEs, treatment-emergent serious adverse events as reported by investigator. 23
Laboratory Abnormalities Through Week 24 Patients, n (%) Total cholesterol Placebo + csdmard Sarilumab + csdmard 150 mg q2w 200 mg q2w (n=184) 6.2 mmol/l (239 mg/dl) 44/181 (24.3) 83/180 (46.1) 81/182 (44.5) 7.74 mmol/l (299 mg/dl) 7/181 (3.9) 20/180 (11.1) 23/182 (12.6) LDL 4.1 mmol/l (158 mg/dl) 27/181 (14.9) 56/179 (31.3) 58/182 (31.9) 4.9 mmol/l (189 mg/dl) 11/181 (6.1) 19/179 (10.6) 28/182 (15.4) Triglycerides 4.6 mmol/l (407 mg/dl) 2/181 (1.1) 13/180 (7.2) 8/182 (4.4) 5.6 mmol/l (496 mg/dl) 1/181 (0.6) 11/180 (6.1) 5/182 (2.7) Lipid levels, no./total (%) Increase in LDL-C from <160 mg/dl to 160 mg/dl a 16/169 (9.5) 48/170 (28.2) 44/172 (25.6) Increase in HDL-C from <60 mg/dl to 60 mg/dl b 32/109 (29.4) 42/106 (39.6) 38/105 (36.2) Statins were initiated in 7 (3.9%) patients in the sarilumab 150 mg q2w group and 8 (4.3%) patients in the sarilumab 200 mg q2w group during the study. No patient in the placebo group initiated statins during the study. csdmard, conventional synthetic disease-modifying antirheumatic drug; HDL, high-density lipoprotein; LDL, low-density lipoprotein; q2w, every 2 weeks; ULN, upper limit of normal. asample size: placebo + csdmard, n=169; sarilumab 150 mg + csdmard, n=170; sarilumab 200 mg + csdmard, n=172. bsample size: placebo + csdmard, n=109; sarilumab 150 mg + csdmard, n=106; sarilumab 200 mg + csdmard, n=105. 24
Mean hemoglobin, g/ml Increase in Hemoglobin Over Time in the Safety Population Placebo + csdmard Sarilumab 150 mg q2w + csdmard Sarilumab 200 mg q2w + csdmard 140 135 130 125 120 BL 2 4 6 8 10 12 16 20 24 Week csdmard, conventional synthetic disease-modifying antirheumatic drug; q2w, every 2 weeks. 25
Mean albumin, g/l Increase in Albumin Over Time in the Safety Population Placebo + csdmard Sarilumab 150 mg q2w + csdmard Sarilumab 200 mg q2w + csdmard 42 41 40 39 38 37 36 35 BL 2 4 6 8 10 12 16 20 24 Week csdmard, conventional synthetic disease-modifying antirheumatic drug; q2w, every 2 weeks. 26
Mean HDL, mmol/l Mean triglycerides, mmol/l Mean cholesterol, mmol/l Mean LDL, mmol/l Mean Total Cholesterol, HDL, LDL, and Total Triglycerides During the TEAE Period in the Safety Population 6 5.8 5.6 Mean cholesterol 3.8 3.65 3.5 3.35 Mean LDL 5.4 3.2 5.2 5 3.05 2.9 2.75 4.8 BL 2 4 8 12 24 Week 2.6 BL 2 4 8 12 24 Week 1.75 1.7 Mean HDL 2.25 2.1 Mean triglycerides 1.65 1.95 1.6 1.8 1.55 1.65 1.5 1.5 1.45 BL 2 4 8 12 24 Week 1.35 BL 2 4 8 12 24 Week csdmard, conventional synthetic disease-modifying antirheumatic drug; HDL, high-density lipoprotein; LDL, low-density lipoprotein; q2w, every 2 weeks; TEAE, treatment-emergent adverse event. 27
Number (%) of Patients With TEAEs by Primary SOC and PT ( 2% in at Least 1 Treatment Group) Placebo Sarilumab + csdmard TEAE, n (%) + csdmard (N=181) 150 mg q2w (N=181) 200 mg q2w (N=184) Any class 90 (49.7) 119 (65.7) 120 (65.2) Infections and infestations 48 (26.5) 40 (22.1) 56 (30.4) Urinary tract infection 12 (6.6) 6 (3.3) 13 (7.1) Nasopharyngitis 9 (5.0) 11 (6.1) 7 (3.8) Pharyngitis 3 (1.7) 2 (1.1) 6 (3.3) Upper respiratory tract infection 6 (3.3) 4 (2.2) 6 (3.3) Influenza 2 (1.1) 2 (1.1) 5 (2.7) Sinusitis 4 (2.2) 3 (1.7) 5 (2.7) Gastroenteritis 3 (1.7) 2 (1.1) 4 (2.2) Cellulitis 1 (0.6) 3 (1.7) 3 (1.6) Oral herpes 0 0 3 (1.6) Pneumonia 0 2 (1.1) 3 (1.6) Conjunctivitis 2 (1.1) 0 2 (1.1) Fungal skin infection 0 0 2 (1.1) Rhinitis 2 (1.1) 1 (0.6) 0 Blood and lymphatic system disorders 9 (5.0) 25 (13.8) 29 (15.8) Neutopenia 2 (1.1) 23 (12.7) 23 (12.5) Thrombocytopenia 0 0 5 (2.7) Leukopenia 0 2 (1.1) 3 (1.6) Anemia 5 (2.8) 0 1 (0.5) csdmard, conventional synthetic disease-modifying antirheumatic drug; PT, preferred term; q2w, every 2 weeks; SOC, system organ class; TEAE, treatment-emergent adverse event. 28
Number (%) of Patients With TEAEs by Primary SOC and PT ( 2% in at Least 1 Treatment Group) (cont) Placebo Sarilumab + csdmard TEAE, n (%) + csdmard (N=181) 150 mg q2w (N=181) 200 mg q2w (N=184) Metabolism and nutrition disorders 7 (3.9) 21 (11.6) 15 (8.2) Hypertriglyceridemia 3 (1.7) 11 ( 6.1) 5 (2.7) Hypercholesterolemia 0 6 (3.3) 4 (2.2) Hyperlipidemia 1 (0.6) 2 (1.1) 3 (1.6) Dyslipidemia 0 4 (2.2) 2 (1.1) Hypokalemia 0 0 2 (1.1) Nervous system disorders 15 (8.3) 12 (6.6) 10 (5.4) Headache 7 (3.9) 5 (2.8) 6 (3.3) Dizziness 4 (2.2) 2 (1.1) 2 (1.1) Convulsion 0 2 (1.1) 0 Paresthesia 0 2 (1.1) 0 Eye disorders 1 (0.6) 5 (2.8) 4 (2.2) Cataract 0 1 (0.6) 2 (1.1) Vascular disorders 8 (4.4) 4 (2.2) 10 (5.4) Hypertension 4 (2.2) 3 (1.7) 8 (4.3) Hot flush 2 (1.1) 0 1 (0.5) Respiratory, thoracic and mediastinal disorders 7 (3.9) 8 (4.4) 13 (7.1) Rhinitis allergic 0 0 2 (1.1) Sinus congestion 2 (1.1) 0 1 (0.5) Gastrointestinal disorders 16 (8.8) 10 (5.5) 26 (14.1) Diarrhea 7 (3.9) 2 (1.1) 6 (3.3) Abdominal distension 0 0 3 (1.6) Aphthous stomatitis 1 (0.6) 0 3 (1.6) Abdominal discomfort 0 0 2 (1.1) Food poisoning 0 0 2 (1.1) Gastritis 0 2 (1.1) 2 (1.1) Mouth ulceration 0 0 2 (1.1) Nausea 3 (1.7) 1 (0.6) 2 (1.1) Abdominal pain 1 (0.6) 3 (1.7) 0 Hemorrhoids 2 (1.1) 0 0 Hepatobiliary disorders 1 (0.6) 1 (0.6) 4 (2.2) Hepatic steatosis 0 0 2 (1.1) Skin and subcutaneous tissue disorders 11 (6.1) 15 (8.3) 11 (6.0) Pruritus generalized 0 1 (0.6) 3 (1.6) Pruritus 0 3 (1.7) 1 (0.5) Dermatitis allergic 0 2 (1.1) 0 Erythema 0 3 (1.7) 0 csdmard, conventional synthetic disease-modifying antirheumatic drug; PT, preferred term; q2w, every 2 weeks; SOC, system organ class; TEAE, treatmentemergent adverse event. 29
Number (%) of Patients With TEAEs by Primary SOC and PT ( 2% in at Least 1 Treatment Group) (cont) Placebo Sarilumab + csdmard TEAE, n (%) + csdmard (N=181) 150 mg q2w (N=181) 200 mg q2w (N=184) Musculoskeletal and connective tissue disorders 22 (12.2) 18 (9.9) 15 (8.2) Rheumatoid arthritis 8 (4.4) 3 (1.7) 4 (2.2) Back pain 1 (0.6) 2 (1.1) 3 (1.6) Arthralgia 0 1 (0.6) 2 (1.1) Musculoskeletal pain 0 1 (0.6) 2 (1.1) Bursitis 2 (1.1) 0 1 (0.5) Intervertebral disc protrusion 0 3 (1.7) 0 Joint swelling 2 (1.1) 1 (0.6) 0 Muscle spasms 3 (1.7) 1 (0.6) 0 Pain in extremity 3 (1.7) 1 (0.6) 0 Renal and urinary disorders 3 (1.7) 3 (1.7) 0 Hematuria 0 2 (1.1) 0 Nephrolithiasis 0 2 (1.1) 0 Reproductive system and breast disorders 5 (2.8) 3 (1.7) 1 (0.5) Metrorrhagia 2 (1.1) 0 0 General disorders and administration site conditions 10 (5.5) 24 (13.3) 22 (12.0) Injection site erythema 0 11 (6.1) 7 (3.8) Injection site pruritus 0 4 (2.2) 5 (2.7) Injection site rash 1 (0.6) 1 (0.6) 3 (1.6) Edema peripheral 1 (0.6) 3 (1.7) 3 (1.6) Pyrexia 0 1 (0.6) 2 (1.1) Investigations 8 (4.4) 19 (10.5) 30 (16.3) Alanine aminotransferase increased 2 (1.1) 5 (2.8) 10 (5.4) Aspartate aminotransferase increased 0 2 (1.1) 6 (3.3) Transaminases increased 0 2 (1.1) 3 (1.6) Blood pressure increased 0 1 (0.6) 2 (1.1) Hepatic enzyme increased 0 0 2 (1.1) Neutrophil count decreased 0 3 (1.7) 2 (1.1) Blood triglycerides increased 0 2 (1.1) 1 (0.5) Injury, poisoning and procedural complications 15 (8.3) 16 (8.8) 15 (8.2) Accidental overdose 5 (2.8) 7 (3.9) 9 (4.9) Arthropod bite 0 2 (1.1) 0 Fall 3 (1.7) 1 (0.6) 0 Ligament sprain 0 2 (1.1) 0 csdmard, conventional synthetic disease-modifying antirheumatic drug; PT, preferred term; q2w, every 2 weeks; SOC, system organ class; TEAE, treatmentemergent adverse event. 30