Interferon Inhibition for Lupus with Anifrolumab: Critical Appraisal of the Evidence Leading to FDA Approval

Abstract

Journal Club Furie R, Khamashta M, Merrill JT, Werth VP, Kalunian K, Brohawn P, et al. Anifrolumab, an anti‐interferon‐α receptor monoclonal antibody, in moderate‐to‐severe systemic lupus erythematosus. Arthritis Rheumatol 2017;69:376‐86. ObjectiveTo assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double‐blind, placebo‐controlled study of adults with moderate‐to‐severe systemic lupus erythematosus (SLE). MethodsPatients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4‐gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI [4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI [4], British Isles Lupus Assessment Group [BILAG]–based Composite Lupus Assessment [BICLA], modified SRI [6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent‐to‐treat (ITT) population and type I IFN–high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2‐sided), within each of the 2 study populations for the primary end point analysis. ResultsThe primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo‐treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ‐specific end points. Herpes zoster was more frequent in the anifrolumab‐treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was ...

Single cell analysis of docosahexaenoic acid suppression of sequential LPS-induced proinflammatory and interferon-regulated gene expression in the macrophage

“…Upregulated IFN1 responses contribute to the development of multiple forms of autoimmunity including lupus, systemic sclerosis, Sjogren’s syndrome ( 77 ). Indeed, successful clinical trials of anifrolumab, an anti-IFNAR monoclonal antibody ( 78 ), led to its approval by the USFDA in 2021 for lupus treatment ( 79 ). Relatedly, in a prior in vivo study, we observed that DHA supplementation significantly reduces IFN1-regulated gene expression in lupus-prone mice induced by exposure to the autoimmune trigger crystalline silica ( 80 ).…”

Ultrarare Variants in DNA Damage Repair and Mitochondrial Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome and Acute Behavioral Regression in Neurodevelopmental Disorders

“…For example, increased IFN-I responses mediated by cGAS-STING due to abnormal clearance of cytosolic DNA and RNA have been implicated in the pathogenesis of SLE and aggressive rheumatoid arthritis [177][178][179][180]. Circulating type I IFN levels are elevated in approximately 50% of patients with SLE and IFN receptor inhibition is an approved therapy [181,182]. A substantial fraction of SLE patients have neuropsychiatric symptoms [183,184].…”

Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients

“…Currently, fewer than half of AYA patients survive R/R AML [16,17,95,98]. While outcomes in patients' OS have improved over time, this improvement has been attributed more to supportive care and disease complications' management, rather than to the development of novel therapeutic regimens [32]. As patients' survival has reached a plateau and the intensification of chemotherapy is not feasible due to treatment-related toxicity, the scientific community has had to introduce novel pathways in resolving this issue [19].…”

“…As patients' survival has reached a plateau and the intensification of chemotherapy is not feasible due to treatment-related toxicity, the scientific community has had to introduce novel pathways in resolving this issue [19]. Standardizing relapse definitions and treatment-response criteria, investigating novel targeted agents, and encouraging pediatric and AYA (including populations with rare biological/molecular subtypes) enrollment in clinical trials gradually improves the diagnostic and therapeutic evaluation of R/R AML in AYAs [32,109]. Towards this direction, additional efforts towards genetic and biological characterization remain necessary.…”

“…Non-targeted techniques, mainly next-generation sequencing, have been powerful in the therapeutic targeting of newly identified mutations [110]. As a result, the genomic landscape of AML has been recently updated for the age group of AYAs [32]. Novel tumor-specific therapeutic approaches with milder adverse effects compared to the standard chemotherapeutic treatment are currently being proposed and tested [110].…”