<p>Spotlight on anifrolumab and its potential for the treatment of moderate-to-severe systemic lupus erythematosus: evidence to date</p>

Abstract

Previous reports have described the appearance of systemic lupus erythematosus (SLE) cases following interferon-α (IFN-α) therapy, IFN-regulated gene expression is significantly increased in SLE, and an association between SLE and gene variants belonging to IFN downstream pathways has been shown. Based on this, targeting of IFN and of their signaling pathways has appeared to be interesting developments within the field of SLE therapy. Different specific type I IFN antagonists have been studied in clinical trials and some of those have already reached Phase III. A potential approach would be to target IFN receptors rather than IFN themselves. Anifrolumab (previously MEDI-546) is a fully human monoclonal antibody (Ab) that binds to subunit 1 of the type I IFN receptor (IFNAR1), blocking the action of different type I IFNs (IFN-α, IFN-β and IFN-ω). This drug has been assessed in 11 clinical studies: 9 in SLE, 1 in systemic sclerosis and 1 in rheumatoid arthritis. In SLE, clinical development reached Phase I for 1 study and Phases II and III for 5 and 3 trials, respectively. The Phase IIb, randomized control trial (RCT), double-blind, placebo-controlled study of adults with moderate-to-severe SLE (MUSE trial) showed positive results on the composite primary endpoint SRI-4. Greater efficacy was seen in patients with high baseline IFN gene signature compared with those with low baseline IFN gene signature. Anifrolumab also demonstrated promising results on cutaneous and arthritic manifestations, especially among patients with a high IFN gene signature. The pivotal Treatment of Uncontrolled Lupus via the Interferon IFN Pathway (TULIP 1 and 2 studies are now completed. In August 2018, the promoter announced that the TULIP 1 Phase III trial did not reach its primary endpoint. The release of the completed but not yet published Phase II studies and of the TULIP pivotal trials results will further inform us on the actual therapeutic potential of anifrolumab.

Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways

“…Although the trial did not see a benefit in Based Composite Lupus Assessment (BICLA), the drug did provoke anti-IFN-a2b serum antibodies and decreased the IFN gene signature in 91% of patients. An anti-IFNAR1 monoclonal antibody, anifrolumab, has been evaluated in 11 clinical trials for SLE (9), Sjögren's (1), and rheumatoid arthritis (1), with encouraging results (53). A recent phase III trial in SLE did not meet its primary endpoint of response, as per the SLE Responder Index; however, the same group conducted another phase III trial using the of British Isles Lupus Assessment Group (BILAG)-BICLA response as the primary endpoint and reported a statistically significant higher percentage of patients having a response as well as seeing a decrease in secondary endpoints, suggesting that a chronic IFNa response in SLE patients may contribute to disease pathogenesis (48).…”

Design and application of single-cell RNA sequencing to study kidney immune cells in lupus nephritis

“…This observation alone cannot provide information on the presence of interferon in inflamed tissue or the contribution of interferon to tissue pathology such as lupus nephritis. The efficacy of targeting type 1 interferons to treat SLE remains under investigation in large clinical trials 27 . Furthermore, using mouse models to inform therapeutic strategies in SLE has had limited success 28 .…”

Current Insights in Cutaneous Lupus Erythematosus Immunopathogenesis

“…Interestingly, the authors found no differences between skin biopsies of patients with and without systemic involvement. Blocking IFNα receptor improved CLASI scores for SLE patients with cutaneous involvement in a phase II trial [ (152,153), reviewed in (154)]; however IFNγ blockade did not improve CLASI scores in DLE patients (155). Single cell resolution may be necessary to elucidate the precise roles of different IFNs in pathogenesis.…”