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Method: This is a 2-part, phase 1, double blind, placebo controlled study to evaluate the safety and PK of multiple IV infusions of sirukumab, a human anti-interleukin-6 mAb in CLE/SLE pts. In Part A, pts with histologically-confirmed CLE were randomized to receive a total of 4 IV infusions of placebo or sirukumab 1, 4, or 10 mg/kg q2w. In Part B, pts with SLE diagnosed by ACR criteria and a SELENA-SLEDAI score of 5 to 12 were randomized to receive a total of 4 IV infusions of placebo or the highest well tolerated sirukumab dose in Part A (10 mg/kg) q2w. Primary evaluations were safety and PK. Secondary evaluations were PD, immune response, and preliminary clinical responses
Result: In Part A, 33 CLE pts were randomized (64% F; 31 Caucasian, 2 Asian; age 29-69; weight 49-100 kg), and 31 were treated. In Part B, 15 SLE pts were randomized and treated (87% F; 9 Caucasian, 6 Asian; age 19-58; weight 46-81 kg). More AEs were reported with sirukumab than placebo (Part A: 21/23 [91%] vs 5/8 [63%], Part B: 9/10 [90%] vs 4/5 [80%]). Sirukumab led to sustained, dose-independent decreases in WBC, ANC (neutropenia), platelets (thrombocytopenia); and minor elevations in total cholesterol. More skin-related AEs occurred with sirukumab 1 and 4 mg/kg than placebo; none occurred with 10 mg/kg. The majority of infectious AEs were mild upper respiratory infections reported similarly between groups in Part A but more often with sirukumab in Part B. More SAEs occurred with sirukumab than placebo (Part A: 3/23 [13%] vs 0/8 [0%], Part B: 2/10 [20%] vs 1/5 [20%]). SAEs reported with sirukumab were Horner’s syndrome, epistaxis followed by iatrogenic wound infection and lung cancer, cholelithiasis, and pneumonia; none were possibly related to study drug except pneumonia. One pt on placebo had an unrelated myocardial infarction. One death occurred from a car accident. Sirukumab showed linear PK at IV doses of 1 to 10 mg/kg in CLE pts. Systemic exposure (Cmax and AUC[day 0-14]) and half-life were comparable between CLE and SLE pts. Sirukumab was not detected in urine samples from SLE pts. CRP and SAA decreased to low median levels by wk 1 and remained low through wk 14 with sirukumab in all pts. Complement C3 and C4 decreased with sirukumab in all pts without associated clinical disease flare. Of 32 pts with evaluable samples, none developed anti-sirukumab antibodies. Decreases in titers of ANA and anti-dsDNA and no other autoantibody changes occurred with sirukumab. No clinical improvement was detected by CLASI, overall BILAG global score, or SELENA-SLEDAI scores. In SLE pts, those treated with sirukumab improved in SF-36 physical scores and had stable DLQI scores while those treated with placebo had stable SF-36 and worsening DLQI.
Conclusion: Treatment with IV infusions of sirukumab was generally safe and well tolerated in both CLE and SLE pts. Sirukumab showed linear PK over the IV dose range of 1 to 10 mg/kg. Systemic exposure and half-life were comparable in CLE and SLE pts. Future studies in pts with more severe disease are needed to clarify the safety profile and efficacy potential of sirukumab.
Disclosure: J. C. Szepietowski, Johnson & Johnson, 2 ; S. Nilganuwong, Johnson & Johnson, 2 ; A. Wozniacka, Johnson & Johnson, 2 ; A. Kuhn, Johnson & Johnson, 2 ; F. Nyberg, Johnson & Johnson, 2 ; J. Szechinski, Johnson & Johnson, 2 ; R. F. van Vollenhoven, Johnson & Johnson, 2 ; A. Bengtsson, Johnson & Johnson, 2 ; A. Reich, Johnson & Johnson, 2 ; D. de Vries, Johnson & Johnson, 3 ; B. van Hartingsveldt, Johnson & Johnson, 3 ; B. Zhou, Johnson & Johnson, 3 ; B. Hsu, Johnson & Johnson, 3 .