Ustekinumab fails to show superiority to placebo in lupus
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Ustekinumab failed to demonstrate superiority to placebo among patients with active systemic lupus erythematosus, according to phase-3 data published in Annals of the Rheumatic Diseases.
“The efficacy and safety of ustekinumab in patients with active SLE was evaluated in a phase 2, randomized, placebo-controlled study,” Ronald F. van Vollenhoven, MD, PhD, of the department of rheumatology at the Amsterdam Rheumatology and Immunology Center, in the Netherlands, and co-authors wrote. “Ustekinumab, a monoclonal antibody inhibiting the IL-12/23 p40 subunit, is approved for patients with moderate-to-severe plaque psoriasis and active psoriatic arthritis and was identified in a previous meta-analysis as being a top candidate for repositioning in SLE.”
To investigate the safety and efficacy of ustekinumab (Stelara, Janssen) in patients with active SLE despite receiving standard-of-care treatment, van Vollenhoven and colleagues conducted a phase-3, randomized, placebo-controlled study. The researchers enrolled patients aged 16 to 75 years with a confirmed diagnosis of SLE and a documented history meeting the Systemic Lupus International Collaborating Clinics classification criteria for 3 or more months before initiating study therapy.
To be included, patients were required to demonstrate an SLE Disease Activity Index 2000 (SLEDAI-2K) of six or more and a baseline SLEDAI-2K of four or more for clinical features while receiving stable doses of standard-of-care medications, including glucocorticoids, antimalarials and immunomodulatory drugs. Patients were excluded from the study if there was an unstable or progressive manifestation of SLE or other inflammatory diseases that could confuse results.
Included patients were randomized 3:2 to receive ustekinumab or placebo. Ustekinumab was administered through an intravenous infusion of about 6 mg per kg at week 0, followed by subcutaneous injections of 90 mg at 8 weeks, and then every 8 weeks after that. Researchers assessed efficacy using the SRI-4 composite response.
The primary endpoint was four or more points of reduction in SLEDAI-2K scores, with no new BILAG A, or no more than one BILAG B, domain scores. Additionally, there could be no worsening of the physician global assessment. Secondary endpoints included active joint assessments and the Functional Assessment of Chronic Illness Therapy-Fatigue score for fatigue.
The researchers enrolled a total of 516 patients, of whom 208 received placebo and 308 received ustekinumab. However, the study was discontinued by the sponsor due to lacking efficacy data.
The present analysis included 289 patients, of whom 173 received ustekiunumab who had, or would have had, a visit at week 52. At week 52, 44% of patients receiving ustekinumab and 56% of patients receiving placebo demonstrated an SRI-4 response. There were no major differences between the groups regarding the secondary endpoints. Through 52 weeks, 70% of patients receiving ustekinumab and 74% of patients receiving placebo therapy reported one or more adverse event.
“Although the phase 2 results appeared robust, the phase 3 LOTUS study met futility criteria and was discontinued early,” van Vollenhoven and colleagues wrote. “The primary and key secondary endpoints were not achieved in the overall study population or in the subpopulations evaluated in these analyses; despite a numerical trend suggesting that steroid tapering was possible to a greater extent in the ustekinumab group compared with the placebo group, there was insufficient evidence to support continuation of development of ustekinumab in patients with SLE.”
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