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Trial of anifrolumab in active systemic lupus erythematosus.

Comment on: Morand EF, Furie R, Tanaka Y, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med. 2019 Dec 18. doi: 10.1056/NEJMoa1912196. [Epub ahead of print]

Commented by: Ricard Cervera, Barcelona, Catalonia, Spain

So far, only one biologic targeted therapy, belimumab, has been approved for systemic lupus erythematosus (SLE) and the development of such therapies for this disease has been constrained by difficulties in trial design (i.e., selection of adequate end-points, use of concomitant medications…) as well as SLE clinical and biologic heterogeneity, thus leading to a record number of trial failures.

Fortunately, research on many promising molecules with potential efficacy in SLE is ongoing and, in 2017, the therapeutic benefit of inhibiting the interferon pathway in patients with SLE was reported in a phase 2 trial of anifrolumab. This is a fully human, IgG1κ monoclonal antibody to type I interferon receptor subunit 1 that inhibits signaling by all type I interferons, including diversity of peripheral-blood gene expression signatures. But, surprisingly, a subsequent phase 3 trial, named TULIP–1 (Treatment of Uncontrolled Lupus via the Interferon Pathway), did not demonstrate a significant effect of this drug on the selected primary end-point, the SLE Response Index (SRI)-4. However, some prespecified secondary end-points, including the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response, favored anifrolumab treatment.

It is important to remind that 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 SLE Disease Activity Index (SLEDAI), no increase of 0.3 points or more in the score on the Physician Global Assessment (PGA) 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.

The current original article reports the successful findings of TULIP-2, a second phase 3 trial of anifrolumab in active SLE using now BICLA response at week 52 as its primary end-point. The authors randomly assigned patients in a 1:1 ratio to receive intravenous anifrolumab (300 mg) or placebo every 4 weeks for 48 weeks. 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. A total of 362 patients received the randomized intervention (180 received anifrolumab and 182 received placebo).

The main results were as follows: 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.

Therefore, this trial shows that monthly administration of anifrolumab resulted in a higher percentage of patients with a BICLA response at week 52, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end-point (SRI-4). Additionally, this drug also allowed the reduction in the glucocorticoid dose and produced reduction in the severity of skin disease. This study also reinforces the importance of careful selection of adequate end-points in SLE trial design.