SAPHNELO: Anifrolumab for Systemic Lupus Erythematosus- Indication, Side Effects and Mechanism of Action

Anifrolumab is the FDA approved antibody therapy for Systemic Lupus Erythematosus

Anifrolumab-fnia is a type I interferon (IFN) receptor antagonist, immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is produced in mouse myeloma cells (NS0) by recombinant DNA technology. The molecular weight is approximately 148 kDa. 

Indication of SAPHNELO/Anifrolumab:

SAPHNELO is a type I interferon (IFN) receptor antagonist indicated for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE), who are receiving standard therapy.

Limitations of Use: 

The efficacy of SAPHNELO has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus. The use of SAPHNELO is not recommended in these situations.

Contraindications

SAPHNELO is contraindicated in patients with a history of anaphylaxis with anifrolumab-fnia

Warning and Precautions

Serious Infections: Serious and sometimes fatal infections have occurred in patients receiving SAPHNELO. SAPHNELO increases the risk of respiratory infections and herpes zoster. Avoid initiating treatment during an active infection. Consider the individual benefit-risk if used in patients with severe or chronic infections. Consider interrupting therapy with SAPHNELO if patients develop a new infection during treatment. 

Hypersensitivity Reactions Including Anaphylaxis: Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported. 

Malignancy: Consider the individual benefit-risk in patients with known risk factors for malignancy prior to prescribing SAPHNELO.

Immunization: Avoid use of live or live-attenuated vaccines in patients receiving SAPHNELO. 

Not Recommended for Use with Other Biologic Therapies. 

Adverse Reaction associated with SAPHNELO/Anifrolumab: 

Most common adverse drug reactions (incidence ≥5%) are nasopharyngitis, upper respiratory tract infections, bronchitis, infusion-related reactions, herpes zoster and cough. (6) 

Formulation of Anifrolumab

SAPHNELO (anifrolumab-fnia) injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow, solution for intravenous use. SAPHNELO contains anifrolumab-fnia at a concentration of 150 mg/mL in a single-dose vial.

Mechanism of Action of  Anifrolumab:

Anifrolumab-fnia is a human IgG1κ monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR) with high specificity and affinity. This binding inhibits type I IFN signaling, thereby blocking the biologic activity of type I IFNs. Anifrolumab-fnia also induces the internalization of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor-mediated type I IFN signaling inhibits IFN responsive gene expression as well as downstream inflammatory and immunological processes. Inhibition of type I IFN blocks plasma cell differentiation and normalizes peripheral T-cell subsets. Type I IFNs play a role in the pathogenesis of SLE. Approximately 60-80% of adult patients with active SLE express elevated levels of type I IFN inducible genes. 

Pharmacodynamics

In patients with SLE, following the administration of anifrolumab-fnia at 300 mg dose, via intravenous infusion every 4 weeks for 52 weeks, neutralization (≥80%) of a type I IFN gene signature was observed from Week 4 to Week 52 in blood samples of patients with elevated levels of type I IFN inducible genes and returned to baseline levels within 8 to 12 weeks following the withdrawal of anifrolumab-fnia at the end of the 52-week treatment period. 

However, the clinical relevance of the type I IFN gene signature neutralization is unclear. In SLE patients with positive anti-dsDNA antibodies at baseline (Trials 2 and 3), treatment with anifrolumab-fnia 300 mg led to numerical reductions in anti-dsDNA antibodies over time through Week 52. In patients with low complement levels (C3 and C4), increases in complement levels were observed in patients receiving anifrolumab-fnia through Week 52. 

Pharmacokinetics

The PK of anifrolumab-fnia was studied in adult patients with SLE following intravenous doses ranging from 100 to 1000 mg once every 4 weeks, and healthy volunteers following a single intravenous dose at 300 mg. Anifrolumab-fnia exhibits non-linear PK in the dose range of 100 mg to 1000 mg with more than dose-proportional increases in the exposure as measured by AUC. Following the 300 mg every 4 weeks intravenous administrations of anifrolumab-fnia, steady-state was reached by Day 85. The accumulation ratio was approximately 1.36 for Cmax and 2.49 for Ctrough. 

Distribution 

Based on population PK analysis, the estimated volume of distribution at a steady state for a typical patient with SLE (69.1 kg) is 6.23 L. 

Elimination 

From population PK analysis, anifrolumab-fnia exhibited non-linear PK due to IFNAR1-mediated drug clearance. Following the administration of anifrolumab-fnia at a dose of 300 mg via intravenous infusion every 4 weeks, the estimated systemic clearance (CL) for anifrolumab-fnia was 0.193 L/day.