Trial of Anifrolumab in Active Systemic Lupus Erythematosus

Abstract

BACKGROUND Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1 investigated for the treatment of systemic lupus erythematosus (SLE), did not have a significant effect on the primary end point in a previous phase 3 trial. The current phase 3 trial used a secondary end point from that trial as the primary end point. METHODS We randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks. The primary end point of this trial was a response at week 52 defined with the use of the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA). A BICLA response requires reduction in any moderate-to-severe baseline disease activity and no worsening in any of nine organ systems in the BILAG index, no worsening on the Systemic Lupus Erythematosus Disease Activity Index, no increase of 0.3 points or more in the score on the Physician Global Assessment of disease activity (on a scale from 0 [no disease activity] to 3 [severe disease]), no discontinuation of the trial intervention, and no use of medications restricted by the protocol. Secondary end points included a BICLA response in patients with a high interferon gene signature at baseline; reductions in the glucocorticoid dose, in the severity of skin disease, and in counts of swollen and tender joints; and the annualized flare rate. RESULTS A total of 362 patients received the randomized intervention: 180 received anifrolumab and 182 received placebo. The percentage of patients who had a BICLA response was 47.8% in the anifrolumab group and 31.5% in the placebo group (difference, 16.3 percentage points; 95% confidence interval, 6.3 to 26.3; P = 0.001). Among patients with a high interferon gene signature, the percentage with a response was 48.0% in the anifrolumab group and 30.7% in the placebo group; among patients with a low interferon gene signature, the percentage was 46.7% and 35.5%, respectively. Secondary end points with respect to the glucocorticoid dose and the severity of skin disease, but not counts of swollen and tender joints and the annualized flare rate, also showed a significant benefit with anifrolumab. Herpes zoster and bronchitis occurred in 7.2% and 12.2% of the patients, respectively, who received anifrolumab. There was one death from pneumonia in the anifrolumab group. CONCLUSIONS Monthly administration of anifrolumab resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT02446899.

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“…Interestingly, the expression and co-expression profiles of BAFF and IL1RN also changed with IFN response status in this longitudinal data (Figure 2E, H). Recently, a phase III clinical trial (TULIP 2, NCT02446899) in SLE patients with a human monoclonal antibody (Anifrolumab) that specifically blocks IFNAR1 (type I interferon receptor subunit 1) was completed 57 . The trial results also suggested that knowing patients' IFN response status before prescribing targeted therapy will be helpful in the clinical setting and in designing further targeted therapies for specific patient groups.…”

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“…Similar results were also obtained in patients with a stronger IFN signature. In the TULIP 2 trial the primary endpoint, BICLA (BILAG‐based Combined Lupus Assessment) response rate at week 52 was significantly higher in the anifrolumab group, regardless of IFN signature, and significant differences were also observed in the improvement of the Cutaneous Lupus Erythematosus Disease Area and Severity Index, glucocorticoid‐sparing effect, and SRI‐4 response rate 13 . There was no remarkable difference in the incidence of adverse events between the anifrolumab and placebo groups, except for herpes zoster and bronchitis, which occurred in 7.2% of patients in the anifrolumab group.…”

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“…Zudem konnte erstmals in einer Phase III Studie (TULIP II) die Überlegenheit des Typ-I-Interferonrezeptor Inhibitors Anifrolumab gegenüber Placebo gezeigt werden [19]. Primärer Endpunkt war das Therapieansprechen gemessen mittels BICLA Response.…”