Phase 3, multicentre, randomised, placebo-controlled study evaluating the efficacy and safety of ustekinumab in patients with systemic lupus erythematosus

Abstract

Objective: Evaluate the efficacy and safety of ustekinumab, an anti-interleukin-12/23 p40 antibody, in a phase 3, randomised, placebo-controlled study of patients with active systemic lupus erythematosus (SLE) despite receiving standard-of-care.

Methods: Active SLE patients (SLE Disease Activity Index 2000 (SLEDAI-2K) ≥6 during screening and SLEDAI-2K ≥4 for clinical features at week 0) despite receiving oral glucocorticoids, antimalarials, or immunomodulatory drugs were randomised (3:2) to receive ustekinumab (intravenous infusion ~6 mg/kg at week 0, followed by subcutaneous injections of ustekinumab 90 mg at week 8 and every 8 weeks) or placebo through week 48. The primary endpoint was SLE Responder Index (SRI)-4 at week 52, and major secondary endpoints included time to flare through week 52 and SRI-4 at week 24.

Results: At baseline, 516 patients were randomised to placebo (n=208) or ustekinumab (n=308). Following the planned interim analysis, the sponsor discontinued the study due to lack of efficacy but no safety concerns. Efficacy analyses included 289 patients (placebo, n=116; ustekinumab, n=173) who completed or would have had a week 52 visit at study discontinuation. At week 52, 44% of ustekinumab patients and 56% of placebo patients had an SRI-4 response; there were no appreciable differences between the treatment groups in the major secondary endpoints. Through week 52, 28% of ustekinumab patients and 32% of placebo patients had a British Isles Lupus Assessment Group flare, with a mean time to first flare of 204.7 and 200.4 days, respectively. Through week 52, 70% of ustekinumab patients and 74% of placebo patients had ≥1 adverse event.

Conclusions: Ustekinumab did not demonstrate superiority over placebo in this population of adults with active SLE; adverse events were consistent with the known safety profile of ustekinumab.

Trial registration number: NCT03517722.

Keywords: autoimmune diseases; biological therapy; lupus erythematosus, systemic.

Conflict of interest statement

Competing interests: RFvV has received grants from Bristol Myers Squibb, GlaxoSmithKline, MSD, Pfizer, Roche, and UCB; consulting fees from AbbVie, AstraZeneca, Biogen, BMS, Galapagos, Janssen, Miltenyi, Pfizer, UCB; honoraria/speaking fees from AbbVie, Galapagos, GlaxoSmithKline, Janssen, Pfizer, R-Pharma, and UCB. KCK has received grants from Acceleron, Alexion, Alpine, Horizon, Idorsia, Kirin, the National Institutes of Health, Provention Bio, Sanford Consortium, and UCB; consulting fees from Amgen, AstraZeneca, Aurinia, Biogen, Bristol Myers Squibb, Eli Lilly, EquilliumBio, Genentech/Roche, Gilead, GlaxoSmithKline, Janssen, Kang Pu, KezarBio, Merck, and Novartis. TD has received consulting fees, speaking fees, and/or honoraria from AbbVie, Celgene/Bristol Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Janssen, Novartis, Genentech/Roche, and UCB and support for conducting clinical studies (paid to the university) from AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Janssen, Novartis, Roche and UCB. BHH has received consulting fees, speaking fees, and/or honoraria from Aurinia, GlaxoSmithKline and UCB. YT has received speaking fees and/or honoraria from AbbVie, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Mitsubishi-Tanabe, and Pfizer; and received research grants from AbbVie, Asahi-Kasei, Boehringer-Ingelheim, Chugai, Daiichi-Sankyo, Eisai, and Takeda. RMG, CS, KF, SG, LS, PG, KHL and QCZ are employees of Janssen Research & Development and own stock in Johnson & Johnson, of which Janssen Research & Development, is a wholly owned subsidiary. PB is an employee of Immunology Strategic Market Access, Janssen Pharmaceutical Companies of Johnson & Johnson and owns stock in Johnson & Johnson.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Patient disposition of LOTUS participants. mFAS, (including patients who either completed their week 52 visit or would have had a week 52 visit at the time of study discontinuation by the sponsor). mFAS, modified full analysis set.

Figure 2

The proportion of patients achieving an SRI-4 composite response at week 52 (A) and week 24 (B), a reduction in glucocorticoid dose at week 40 that was sustained through week 52 (C), joint response at week 52 (D), CLASI response at week 52 (E), and a reduction in glucocorticoid dose at week 40 that was sustained through week 52 together with an SRI-4 composite response at week 52 (F). Analyses were performed using the modified Full Analysis Set population, excluding patients whose week 52 visit was projected to occur after the early study discontinuation by the sponsor. CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; SRI-4, Systemic Lupus Erythematosus Responder Index-4.

Figure 3

Time to first BILAG flare. BILAG, British Isles Lupus Assessment Group

Figure 4

Baseline serum concentrations of IFNα, IFNγ, p40, IL-17F and IL-22 in LOTUS patients and healthy controls and median change from baseline in serum concentrations of IFNγ and p40 through week 24. Each box represents the 25th to 75th percentiles. Lines inside the boxes represent the median. The upper line extends to the largest value ≤1.5 × IQR; the lower line extends to the smallest value ≤1.5 × IQR. Data beyond the end of the lines represents outlier points. **P