Objectives To determine the efficacy and safety of SC sirukumab (SRM) dose regimens & to describe PK & PD in active RA pts in a Ph2 dose-ranging Part B study.
Methods Pts w/ active RA despite MTX were randomized: (1) PBO q2w at wks 0–10, then SRM 100mg q2w at wks 12–24; (2) SRM 100mg q2w at wks 0–24; (3) SRM 100mg q4w at wks 0–24; (4) SRM 50mg q4w at wks 0–24; or (5) SRM 25mg q4w at wks 0–24. Primary endpt ACR50 at wk12, compared btw each active grp vs PBO. Key secondary endpts: change from baseline (BL) in DAS28 (CRP) at wk12, serum SRM PK, & % change from BL in serum CRP at wk2.
Results In Part B, 151 pts were randomized & treated. 85% female, 60% Caucasian, 21% Japanese. At BL, mean age:53±11yrs, mean weight:69±15kg, mean DAS28 (CRP):5.9±0.9, & median serum CRP:1.7mg/dL. 26 (87%) PBO pts crossed over to SRM 100mg q2w at wk12. At wk12, SRM sig improved ACR50 (overall p=0.010) & sig decreased DAS28 (p<0.001). At wk12, higher % of pts achieved moderate/good DAS28 (CRP) responses in each grp (93.4%, 86.6%, 90.0%, & 83.9% in SRM 100mg q2w, 100mg q4w, 50mg q4w, & 25mg q4w grps, resp) compared w/ PBO (60.0%). Stat sig (p<0.05) was achieved in SRM 100mg q2w & 50mg q4w tx grps. SRM PK were linear over SC dose range of 25–100mg. PK were generally consistent btw Caucasians & Japanese. Mean serum CRP decreased>80% from BL w/ SRM at wk2 & remained suppressed thru wk24. Thru wk38, AEs occurred more often w/ SRM than PBO (81 vs 67%), including minor infections/infestations (31 vs 13%), GI disorders (19 vs 10%), & injection site reactions (16 vs 3%). Leukopenia (19, 13% [1 NCI Gr 3]), neutropenia (5, 3% [3 Gr 3]), thrombocytopenia (3, 2% [1 Gr 3, 1 Gr 4]), & lymphopenia (2, 1%, [1 Gr 3, 1 Gr 4]) were reported w/ SRM. ALT (8 Gr 3, 7%) & AST (1 Gr 3, 1%) elevations not associated w/ increased bilirubin; & sustained increase from BL starting at wk2 in total cholesterol (mean SRM vs PBO: 19%±17% vs -5%±12%) & LDL (20%±20% vs -4%±22%) were seen w/ SRM. These lab abnormalities occurred w/o dose relationship or short term clinical sequelae. SAEs were more common w/ PBO (4, 13%) than SRM (13, 9%); majority were infections. 1 pt died of unrelated brain aneurysm. 4/136 (3%; 2 100mg q4w, 2 PBO→100mg q2w) evaluable pts had antibodies to SRM thru wk38; 3 of these pts were ACR50 responders at wk24, 0 had injection site reactions.
Conclusions SRM was efficacious & generally well tolerated. SRM PK were linear over SC regimens ranging from 25 to 100mg.
Disclosure of Interest B. Hsu Employee of: Janssen Research & Development, LLC, S. Sheng Employee of: Janssen Research & Development, LLC, J. Smolen Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study, M. Weinblatt Grant/Research support from: Investigators for Janssen Research & Development, LLC sponsored clinical study