Safety and Tolerability of Subcutaneous Sarilumab and Intravenous Tocilizumab in Patients With RA

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Abigail George
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1 Sfety nd Tolerbility of Subcutneous Srilumb nd Intrvenous Tocilizumb in Ptients With RA Pul Emery, 1 Jun Rondon, 2 Anju Grg, 3 Hubert vn Hoogstrten, 3 Neil M.H. Grhm, 4 Ming Liu, 4 Nncy Liu, 3 Jnie Prrino, 4 Alberto Spindler 5 1 University of Leeds, Leeds, UK; 2 Arthritis nd Rheumtic Diseses of South Florid, Pembroke Pines, FL, USA; 3 Snofi, Bridgewter, NJ, USA; 4 Regeneron Phrmceuticls, Inc, Trrytown, NY, USA; 5 Universidd Ncionl de Tucumán, Tucumán, Argentin

2 Disclosures Pul Emery hs received reserch grnts nd consulting fees from Abbott, AbbVie, BMS, Pfizer, UCB, MSD, Roche, Novrtis, Smsung, Tked, Eli Lilly, Snofi, nd Regeneron Phrmceuticls, Inc Anju Grg, Hubert vn Hoogstrten, nd Nncy Liu re employees of Snofi nd my own stock nd/or stock options in the compny Neil M.H. Grhm nd Jnie Prrino re employees of Regeneron Phrmceuticls, Inc, nd my own stock nd/or stock options in the compny Jun Rondon, Ming Liu, nd Alberto Spindler hve nothing to disclose This study ws sponsored by Snofi nd Regeneron Phrmceuticls, Inc. Poster development support ws provided by Kristi Porter, PhD, MedThink SciCom, nd funded by Snofi nd Regeneron Phrmceuticls, Inc 2

3 Bckground Srilumb nd tocilizumb re monoclonl ntibodies directed ginst the IL-6 receptor Srilumb is n investigtionl humn monoclonl ntibody Tocilizumb is humnized monoclonl ntibody pproved for tretment of moderte-to-severe RA Srilumb + MTX hs previously demonstrted efficcy in ptients with moderte-to-severe RA nd ws generlly well tolerted 1,2 The sfety nd tolerbility of srilumb nd tocilizumb in dults with RA ws exmined in 2 studies: Study 1309 nd ASCERTAIN IL, interleukin; MTX, methotrexte; RA, rheumtoid rthritis. Study 1309, NCT ASCERTAIN, NCT Genovese et l. Arthritis Rheumtol. 2015;67: Fleischmnn et l. Presented t: ACR; November 7-11, 2015; Sn Frncisco, CA. 3

4 Study 1309 Study Design 6-week, open-lbel, rndomized, single-dose sfety study of srilumb nd tocilizumb 6 weeks N=105 Rndomized 1:1:1:1 Adults with RA on stble MTX tretment R Srilumb 150 mg SC + MTX (n=26) Srilumb 200 mg SC + MTX (n=27) Tocilizumb 4 mg/kg IV + MTX (n=26) Tocilizumb 8 mg/kg IV + MTX (n=26) Screening Bseline Follow-up Visit 1 2 weeks Dy 1 single dose b D2 D3 D4 D5 D6 D7 D9 D11 D13 D15 D19 D22 D29 D43 IV, intrvenously; MTX, methotrexte; RA, rheumtoid rthritis; SC, subcutneously. Prior biologic use permitted if stopped within protocol-specified time period prior to screening. b Smples were collected pre-dose nd t 1, 4, nd 8 hours fter single drug dosing on dy 1. 4

5 ASCERTAIN Study Design 24-week rndomized, double-blind, double-dummy sfety study of srilumb nd tocilizumb 24 weeks N=202 Rndomized 1:1:2 Indequte response or intolernce to nti-tnf R Srilumb 150 mg SC q2w + csdmards (n=49) Srilumb 200 mg SC q2w + csdmards (n=51) Tocilizumb IV q4w + csdmards (n=102) Screening Bseline Visit 1 4 weeks D1 Wk 2 Wk 4 Wk 6 Wk 8 Wk 10 Wk 12 Wk 14 Wk 16 Wk 18 Wk 20 Wk 22 Wk 24 Dosing schedule SC srilumb/plcebo q2w IV tocilizumb/plcebo q4w Hemtology lb ssessments Every 2 weeks In ccordnce with US prescribing informtion, tocilizumb IV q4w incresed to 8 mg/kg from 4 mg/kg bsed on clinicl response s ssessed by investigtor. csdmard, non-biologic disese-modifying ntirheumtic drug; TNF, tumor necrosis fctor. 5

6 Study 1309 nd ASCERTAIN Key Inclusion nd Exclusion Criteri Inclusion criteri Exclusion criteri RA dignosis 3 months ACR functionl clss I-III Age <18 yers History of severe systemic RA, juvenile idiopthic rthritis, or rthritis onset before ge 16; or pst or current utoimmune, inflmmtory systemic, or loclized joint disese other thn RA Prenterl or intr-rticulr corticosteroids within 4 weeks of screening Orl corticosteroids (ie, >10 mg of prednisone or equivlent per dy), or chnge in dosge within 4 weeks before rndomiztion History of lcohol or drug buse within 5 yers of screening Prticiption in ny clinicl reserch study of n investigtionl drug within 5 hlf-lives or 60 dys of screening RA, rheumtoid rthritis. 6

7 Increses in Tocilizumb Dose During ASCERTAIN A totl of 102 ptients were rndomized to the tocilizumb IV q4w group 61% of ptients (n=62) receiving tocilizumb incresed their dose from 4 mg/kg to 8 mg/kg t lest once during the tretment period Tocilizumb IV q4w + csdmards (n=102) Tocilizumb 4 mg/kg Remined on this dose throughout the study (n=40) Tocilizumb 4/8 mg/kg Incresed dose to 8 mg/kg (n=62) Tocilizumb 4/8 mg/kg Incresed to 8 mg/kg t week 4 nd mintined dose (n=39) Either incresed dose to 8 mg/kg fter week 4 or subsequently reduced dose to 4 mg/kg (n=23) csdmard, non-biologic disese-modifying ntirheumtic drug; IV, intrvenously; q4w, every 4 weeks. Subset of ptients included in further lbortory nlyses of bsolute neutrophil count, lnine minotrnsferse, nd low-density lipoprotein. 7

8 Study 1309 nd ASCERTAIN Bseline Demogrphics Tocilizumb 4 mg/kg IV (n=25) Study 1309 Tocilizumb 8 mg/kg IV (n=24) Srilumb 150 mg SC (n=26) Srilumb 200 mg SC (n=26) Tocilizumb IV q4w (n=102) ASCERTAIN Srilumb 150 mg SC q2w (n=49) Srilumb 200 mg SC q2w (n=51) Age, men, y Femle, % (n) 88.0 (22) 96.8 (23) 76.9 (20) 84.6 (22) 80.4 (82) 83.7 (41) 76.5 (39) Rce, % (n) Cucsin 84.0 (21) 83.3 (20) 84.6 (22) 80.8 (21) 92.2 (94) 95.9 (47) 90.2 (46) RA durtion, men, y ANC, bsolute neutrophil count; IV, intrvenously; RA, rheumtoid rthritis; SC, subcutneously. Tocilizumb incresed to 8 mg/kg from 4 mg/kg bsed on clinicl response s ssessed by investigtor. 8

9 Overview of Adverse Events in Study 1309 nd ASCERTAIN Study 1309 ASCERTAIN Ptients, % (n) Tocilizumb 4 mg/kg IV (n=25) Tocilizumb 8 mg/kg IV (n=24) Srilumb 150 mg SC (n=26) Srilumb 200 mg SC (n=26) Tocilizumb IV q4w b (n=102) Srilumb 150 mg SC q2w (n=49) Srilumb 200 mg SC q2w (n=51) TEAEs 32.0 (8) 50.0 (12) 38.5 (10) 46.2 (12) 66.7 (68) 67.3 (33) 70.6 (36) SAEs (1) (7) 2.0 (1) 5.9 (3) Serious infections (2) (1) TEAEs leding to deth (1) 0 0 TEAEs leding to NA NA NA NA 3.9 (4) 12.2 (6) 15.7 (8) tretment D/C In ASCERTAIN, 5 ptients on srilumb discontinued the study becuse of lbortory bnormlities c 3 ptients who resumed SC injections were discontinued becuse IV infusion could not be resumed within the protocol-specified window; these ptients were identified s SC srilumb ptients fter unblinding 2 ptients on srilumb in ASCERTAIN permnently discontinued becuse of injection site rections 1 ptient on srilumb in ASCERTAIN hd n infusion rection while receiving plcebo IV In 6 remining ptients who discontinued srilumb in ASCERTAIN due to other TEAEs, no clinicl ptterns were observed NA, not pplicble; SAE, serious dverse event; TEAE, tretment-emergent dverse event. Single dose of srilumb SC or tocilizumb IV. b Tocilizumb incresed to 8 mg/kg from 4 mg/kg bsed on clinicl response s ssessed by investigtor. c Lbortory bnormlities were neutropeni, leukopeni, nd incresed trnsminses. 9

10 Frequently Reported Adverse Events in Study 1309 (>2 Ptients Across Tretment Groups) Ptients, % (n) Tocilizumb 4 mg/kg IV (n=25) Tocilizumb 8 mg/kg IV (n=24) Srilumb 150 mg SC (n=26) Srilumb 200 mg SC (n=26) Neutropeni 12.0 (3) 25.0 (6) 15.4 (4) 26.9 (7) Hedche 12.0 (3) Upper respirtory trct infection 4.0 (1) 8.3 (2) 0 0 IV, intrvenously; SC, subcutneously. 10

11 Frequently Reported Adverse Events in ASCERTAIN ( 5% in t Lest 1 Tretment Group) Ptients, % (n) Tocilizumb IV q4w (n=102) Srilumb 150 mg SC q2w (n=49) Srilumb 200 mg SC q2w (n=51) Neutropeni 3.9 (4) 12.2 (6) 15.7 (8) Injection site erythem 1.0 (1) 8.2 (4) 7.8 (4) Nsophryngitis 3.9 (4) 12.2 (6) 5.9 (3) Accidentl overdose 8.8 (9) 2.0 (1) 5.9 (3) Dizziness 3.9 (4) 2.0 (1) 5.9 (3) Urinry trct infection 5.9 (6) 8.2 (4) 3.9 (2) Upper respirtory trct infection 6.9 (7) 4.1 (2) 2.0 (1) Hypercholesterolemi 5.9 (6) 4.1 (2) 2.0 (1) Nuse 6.9 (7) 2.0 (1) 2.0 (1) Gstroenteritis 1.0 (1) 6.1 (3) 0 Rheumtoid rthritis 5.9 (6) 2.0 (1) 0 IV, intrvenously; SC, subcutneously. Tocilizumb incresed to 8 mg/kg from 4 mg/kg bsed on clinicl response s ssessed by investigtor. 11

12 Overview of Lbortory Chnges in Study 1309 nd ASCERTAIN Ptients, % (n) ANC b Tocilizumb 4 mg/kg IV (n=25) Tocilizumb 8 mg/kg IV (n=24) Study 1309 Srilumb 150 mg SC (n=26) Srilumb 200 mg SC (n=26) Tocilizumb IV q4w (n=102) ASCERTAIN Srilumb 150 mg SC q2w (n=49) Srilumb 200 mg SC q2w (n=51) <1.0 Gig/L 12.0 (3) 25.0 (6) 15.4 (4) 26.9 (7) 1.0 (1) 6.1 (3) 9.8 (5) ALT c >3 times ULN (2) (1) 2.9 (3) 4.3 (2) 5.9 (3) Totl cholesterol d 6.2 mmol/l 36.0 (9) 25.0 (6) 34.6 (9) 42.3 (11) 49.5 (50) 56.3 (27) 45.1 (23) ALT, lnine minotrnsferse; ANC, bsolute neutrophil count; IV, intrvenously; SC, subcutneously; ULN upper limit of norml. Tocilizumb incresed to 8 mg/kg from 4 mg/kg bsed on clinicl response s ssessed by investigtor. b For ANC in ASCERTAIN, N=48 for srilumb 150 SC. c For ALT in ASCERTAIN, N=101 for tocilizumb 4 mg/kg IV; nd N=47 for srilumb 150 mg SC. d For totl cholesterol in ASCERTAIN, N=101 for tocilizumb 4 mg/kg IV; nd N=48 for srilumb 150 mg SC. 12

13 Men percent chnge from bseline in ANC Men Percent Chnge From Bseline in Absolute Neutrophil Count by Tretment nd Visit in Study 1309 (Dys 1-7) Mgnitude nd time to onset for decresed ANC were similr cross the srilumb nd tocilizumb groups 12.5 Srilumb 150 mg SC (n=26) Tocilizumb 4 mg/kg IV (n=25) Srilumb 200 mg SC (n=26) Tocilizumb 8 mg/kg IV (n=24) BL * 8h Dy ANC, bsolute neutrophil count; IV, intrvenously; SC, subcutneously. *There were 4 smpling points on dy 1: bseline, 1 hour, 4 hours, nd 8 hours post-dose. 13

14 Men percent chnge from bseline in ANC Men Percent Chnge From Bseline in Absolute Neutrophil Count by Tretment nd Visit in Study 1309 (Dys 1-43) The timing of the trend for return to bseline ws consistent with the dosing intervl for both srilumb (q2w) nd tocilizumb (q4w) 10 Srilumb 150 mg SC (n=26) Tocilizumb 4 mg/kg IV (n=25) Srilumb 200 mg SC (n=26) Tocilizumb 8 mg/kg IV (n=24) Dy ANC, bsolute neutrophil count; IV, intrvenously; q2w, every 2 weeks; q4w, every 4 weeks; SC, subcutneously. 14

15 Men chnge from bseline in ANC Men Chnge From Bseline in ANC in ASCERTAIN Men chnge for srilumb ws within the rnge observed with tocilizumb Srilumb 150 mg SC q2w (n=49) Tocilizumb 4 mg/kg IV q4w (n=40) Srilumb 200 mg SC q2w (n=51) Tocilizumb 4/8 mg/kg IV q4w (n=39) BL Week ANC, bsolute neutrophil count; IV, intrvenously; SC, subcutneously. Tocilizumb incresed to 8 mg/kg from 4 mg/kg bsed on clinicl response s ssessed by investigtor. 15

16 Men chnge from bseline in ALT Men Chnge From Bseline in ALT in ASCERTAIN Men chnge for srilumb ws within the rnge observed with tocilizumb 20 Srilumb 150 mg SC q2w (n=49) Tocilizumb 4 mg/kg IV q4w (n=40) Srilumb 200 mg SC q2w (n=51) Tocilizumb 4/8 mg/kg IV q4w (n=39) BL Week ALT, lnine minotrnsferse; IV, intrvenously; SC, subcutneously. Tocilizumb incresed to 8 mg/kg from 4 mg/kg bsed on clinicl response s ssessed by investigtor. 16

17 Men chnge from bseline in LDL Men Chnge From Bseline in LDL in ASCERTAIN Men chnge for srilumb ws within the rnge observed with tocilizumb Srilumb 150 mg SC q2w (n=49) Tocilizumb 4 mg/kg IV q4w (n=40) Srilumb 200 mg SC q2w (n=51) Tocilizumb 4/8 mg/kg IV q4w (n=39) BL Week IV, intrvenously; LDL, low-density lipoprotein; SC, subcutneously. Tocilizumb incresed to 8 mg/kg from 4 mg/kg bsed on clinicl response s ssessed by investigtor. 17

18 Conclusions No cliniclly meningful differences in dverse events were observed between the srilumb nd tocilizumb tretment groups Lbortory chnges noted in the srilumb groups were within the sme rnge s those noted in the tocilizumb groups In Study 1309, chnges in ANC (incidence of ANC <1.0 Gig/L, time to onset for decrese, ndir vlue, nd time to ndir vlue) were similr for srilumb nd tocilizumb In ASCERTAIN, differences in incidence of ANC <1.0 Gig/L between srilumb nd tocilizumb groups my reflect differences in dosing intervl (q2w for srilumb, q4w for tocilizumb) relted to smpling schedule (every 2 weeks) Infections did not pper to be ssocited with decresed ANC ANC, bsolute neutrophil count; q2w, every 2 weeks; q4w, every 4 weeks. 18

19 Bckup 19

20 ACR response, % Explortory Efficcy Anlyses (LOCF) t Week 24 Were Generlly Similr Across Tretment Groups Tocilizumb IV q4w (n=102) b Srilumb 150 mg SC q2w (n=49) Srilumb 200 mg SC q2w (n=51) ACR20 t week Percentge of ptients chieving DAS28 remission in the srilumb 150 nd 200 mg tretment groups (29% nd 31%) ws similr to tht in the tocilizumb group (29%) DAS28, 28-joint count disese ctivity score; IV, intrvenously; q2w, every 2 weeks; q4w, every 4 weeks; SC, subcutneously. Missing dt for ACR response rtes were imputed using the lst observtion crried forwrd (LOCF) pproch to ccount for higher discontinution rtes in the srilumb groups. b Tocilizumb incresed to 8 mg/kg from 4 mg/kg bsed on clinicl response s ssessed by investigtor. 20

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