Anifrolumab is one of three anti-type-1 interferon agents currently being studied as a potential treatment for systemic lupus erythematosus (SLE). Initial in vivo studies observed higher levels of serum interferon (IFN) in patients with autoimmune disease as opposed to those of healthy controls. Further genetic analyses identified a consistent upregulation of IFN gene signatures in peripheral mononuclear cells of SLE patients. This signature was inducible by IFN, repressed with glucocorticoids, and possibly correlated with disease severity. Therefore, specific IFN gene signatures have been used in clinical trials as diagnostic and pharmacodynamic biomarkers in SLE.
Anifrolumab has gained traction as a promising drug for SLE, as demonstrated in the MUSE study (phase IIb), TULIP-1 (phase III), and TULIP-2 (phase III). Though TULIP-1 did not meet its primary endpoint, results from MUSE and TULIP-2 suggest that clinical and immunological improvements can be achieved with administration of anifrolumab up to 48 weeks in SLE patients with mostly high type 1 IFN gene signatures. Both experimental and control groups had concurrent background immunosuppressant therapy. Clinical benefits were shown through multi-organ and symptomatic assessments. On a molecular level, there was the neutralization of IFN gene signatures and improvements in levels of anti-dsDNA antibodies and complement levels, though statistical significance was not formally assessed.
The U.S Food and Drug Administration has not yet approved Anifrolumab. Its promoter plans to file for approval in 2020.
Anifrolumab is a humanized IgG1k monoclonal antibody that binds to subunit 1 of the type 1 IFN receptor (IFNAR1). It inhibits the formation of an IFN/IFNAR complex and subsequent gene transcription. As opposed to other anti-type 1 IFN agents that aim only to neutralize IFN alpha, anifrolumab antagonizes the receptor responsible for cellular signaling induced by IFN alpha, IFN beta, IFN epsilon, IFN kappa, and IFN omega.
IFN alpha is the predominant type 1 IFN implicated in SLE pathogenesis. As a pleiotropic cytokine secreted by plasmacytoid dendritic cells, IFN alpha is responsible for monocyte maturation, neutrophilic NETosis, and polyclonal B-cell expansion and differentiation. A cascade of events ensues, which includes inflammatory cytokine production, immune complex deposition, and complement activation. IFN alpha has additional anti-viral properties, inhibiting viral DNA, and RNA replication. A comprehensive overview of the pathogenesis in SLE is reviewed elsewhere.
Anifrolumab has shown to correct defects of the innate and adaptive immune system. SLE patients, especially those with high type 1 IFN gene signature status, had altered protein expression, the reversal of cytopenias, and normalization of immune cell populations when treated with anifrolumab.
Two routes of administration, subcutaneous (SC) and intravenous (IV), have been studied in human subjects. In a phase I study, anifrolumab 300 mg SC achieved 87% of the IV administration exposure as measured by area under the serum concentration-time curve (AUC). It exhibited approximate linear kinetics as maximum serum concentration (Cmax) increased proportionally with an escalation of anifrolumab dose (300 mg to 600 mg). Time to reach maximum concentrations (Tmax) was 4.1 days, which was consistent with the literature on the pharmacokinetics of SC IgG1 monoclonal antibodies. Anifrolumab 300 mg IV appeared to be more efficacious as it achieved a higher Cmax and shorter Tmax. Researchers did not measure bioavailability in this study; however, there was a quantifiable serum anifrolumab concentration in the treatment groups at least 28 days after the initial dose. Serum concentrations dropped below a detectable threshold by 84 days post-dose. In the MUSE study, anifrolumab 300 or 1000 mg IV was administered every four weeks for 48 weeks to the treatment groups. Interestingly, it exhibited non-linear pharmacokinetics via trends in trough concentrations. Subsequently, a regimen of anifrolumab 150 mg to 300 mg IV every four weeks for 48 weeks was chosen for phase III clinical trials. This decision was made due to the higher incidences of certain infections and no gain in efficacy with higher doses of anifrolumab (i.e., 1000 mg).
The most commonly reported adverse effects include upper respiratory tract infection, nasopharyngitis, infusion-related reaction, bronchitis, and urinary tract infection. Other effects include sinusitis, arthralgia, back pain, and cough. Notably, the incidence of herpes zoster was higher with anifrolumab compared to that of placebo. There were no significant differences in rates of serious nonopportunistic infections, influenza, malignancy, major cardiovascular events, and tuberculosis between the experimental and control groups. Phase IV clinical trials would be particularly helpful in assessing the long-term adverse effects of anifrolumab.
There is no clinical trial data of anifrolumab use in pediatrics, pregnancy, and patients with renal/hepatic impairments. Additionally, researchers excluded patients with active severe lupus nephritis or neuropsychiatric SLE in clinical trials. Thus, at the current moment, anifrolumab should not be administered in this subset of populations.
Due to anifrolumab’s side effect profile, clinicians should exercise caution in patients with an active infection or a history of herpes zoster.
Drug effects are measured primarily with clinical response. Examples of assessments utilized in clinical trials to measure efficacy include the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), SLE responder index (SRI), Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), counts of swollen and tender joints, reductions in glucocorticoid dose, and annual flare rates.
Trending IFN titers, IFN gene signatures, anti-dsDNA antibodies, and complement as parameters to monitor disease activity following anifrolumab administration remain unclear.
Anifrolumab is safe, tolerable, and effective for the treatment of systemic lupus erythematosus. In MUSE and TULIP-1, at higher anifrolumab doses, there were numeric increases of serious adverse events and adverse events leading to study discontinuation. However, statistical significance was not evaluated. To date, there is no distinct anifrolumab serum level that predicts effectiveness and toxicity. Routine measuring of serum levels in clinical practice remains unclear. There is no antidote available. Phase IV clinical trials would be helpful in assessing the possible toxic effects of anifrolumab.
SLE is a heterogeneous condition composed of many responsible biochemical pathways and a wide array of phenotypes. A multidisciplinary and multimodal approach to treating SLE is necessary. Agents against multiple targets and/or personalized medicine through genomic analyses can improve therapeutic outcomes. Though our understanding of SLE pathophysiology continues to evolve, many SLE trials have failed to meet their primary endpoints. These failures could be from flaws in the drug, trial design, or outcome measures. If approved by the U.S Food and Drug Administration, anifrolumab should only be used as adjunctive therapy to standard immunosuppressants in adults aged 18 to 70 with SLE. Future clinical trials exploring the use of anifrolumab in lupus nephritis and neuropsychiatric SLE are needed to expand clinical indication. Before using anifrolumab, healthcare providers should conduct a thorough history and physical to assess baseline clinical status. Patients should be vigilant in monitoring for signs of infections, particularly herpes zoster. Overall, anifrolumab is a novel IFNAR1 antagonist that can assist in achieving clinical remission or low disease activity in patients with SLE.
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