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Lack of efficacy of ustekinumab in a phase 3 randomised controlled trial in patients with systemic lupus erythematosus

Comment on: “Phase 3, multicentre, randomised, placebo-controlled study evaluating the efficacy and safety of ustekinumab in patients with systemic lupus erythematosus” (Ann Rheum Dis. 2022; doi: 10.1136/ard-2022-222858)
Commented by: Maria G. Tektonidou, Professor of Rheumatology, First Department of Propaedeutic Internal Medicine, Laiko Hospital, Medical School, National and Kapodistrian University of Athens, Greece

Patients with systemic lupus erythematosus (SLE) carry an increased disease burden and treatment of the disease remains challenging, illustrated by the fact that only a fraction of patients manage to attain disease remission in clinical practice. This unmet need highlights the need for new, effective therapies. In this regard, an earlier phase 2 study of ustekinumab (UST), a monoclonal antibody inhibiting the interleukin-12/23 p40 subunit already approved for patients with moderate-to-severe plaque psoriasis and active psoriatic arthritis, had demonstrated efficacy in patients with active SLE. Elevated levels of interleukin-12 and -23 have been found in serum and tissue samples from patients with SLE, providing the scientific rationale for testing inhibition of this pathway in lupus. Following the successful phase 2 trial, a larger phase 3 study (LOTUS) was carried out to test UST efficacy in patients with SLE.
The trial included adult patients with active SLE (screening SLEDAI-2K ≥ 6 and baseline clinical SLEDAI-2K ≥ 4), despite receiving stable doses of at least one the following: oral glucocorticoids (≤20 mg/day prednisone or equivalent), antimalarials, or immunomodulatory drugs (mycophenolate mofetil, azathioprine methotrexate). Patients also had to manifest ≥ 1 BILAG A and/or ≥ 2 BILAG B domain scores at screening and a Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity score ≥ 4 or ≥ 4 joints with pain and signs of inflammation at screening. They were randomised (3:2) to receive UST (IV of ~6 mg/kg at week 0, then SC injections of 90 mg at week 8 and every 8 weeks thereafter) or placebo, with crossover to ustekinumab at week 52. The primary endpoint of the study was the proportion of patients achieving an SRI-4 composite response at week 52. Secondary endpoints included time to first flare (≥1 new BILAG A or ≥2 new BILAG B scores) through week 52 and proportion of patients with an SRI-4 at week 24, among others.
Sadly, the study was prematurely terminated by the sponsor following a pre-planned interim analysis (24 weeks after ~50% of the planned enrolment had been randomised) showing lack of drug efficacy. Specifically, in a modified full analysis set population, 44% of UST patients and 56% of placebo patients had reached an SRI-4 response at week 52 Additionally, over 52 weeks, 28% of patients in the UST group and 32% of patients in the placebo group had a BILAG flare. Finally, no significant differences between treatment groups were found in the rates for SRI-4 at week 24 or improvement of joint or CLASI scores at week 52. No particular safety signals were raised, in line with the well-known safety profile of UST from previous trials and real-life clinical practice.

A number of reasons may have accounted for the disappointing results of the LOTUS study and the discordant results between the latter and the earlier (and smaller) phase 2 trial. Patients in LOTUS in general had more swollen/tender joints and more severe skin disease, and those randomised to UST had more BILAG A domain manifestations (47 vs 38%), which may have proved harder to treat. Also, a glucocorticoid tapering regimen was not mandatory as per study design, which may have accounted for the particularly high response rate in the placebo group (56%), higher than the respective rates of the placebo arms in recent SLE trials (e.g. 48% in both baricitinib and belimumab trials). No matter the reason, data from the LOTUS study were insufficient to support further development of UST in SLE, adding to the string of failed clinical trials in the disease.

Reference: van Vollenhoven RF, Kalunian KC, Dörner T, et al. Phase 3, multicentre, randomised, placebo-controlled study evaluating the efficacy and safety of ustekinumab in patients with systemic lupus erythematosus. Ann Rheum Dis 2022 Jul 7; doi: 10.1136/ard-2022-222858. Online ahead of print.