Repositioning Candidate Details
| Candidate ID: | R1424 |
| Source ID: | DB11976 |
| Source Type: | approved; investigational |
| Compound Type: | biotech |
| Compound Name: | Anifrolumab |
| Synonyms: | Anifrolumab; anifrolumab-fnia |
| Molecular Formula: | -- |
| SMILES: | -- |
| DrugBank Description: | Anifrolumab, or MEDI-546, is a type 1 interferon receptor (IFNAR) inhibiting IgG1κ monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus. The standard therapy for systemic lupus erythematosus consists of antimalarials like , glucocorticoids like , and disease modifying antirheumatic drugs like . Three monoclonal antibodies (anifrolumab, , and ) that target the type 1 interferon pathway entered clinical trials as potential treatments for systemic lupus erythematosus, but so far only anifrolumab has been approved. The design of early clinical trials of anti-interferon treatments such as anifrolumab, rontalizumab, and sifalimumab have come under criticism. The design of the clinical trials use different definitions of autoantibody positivity, making comparison between trials difficult; all trials involve large portions of patients also using corticosteroids, which may alter patient responses in the experimental and placebo groups; and patient populations were largely homogenous, which may have increased the odds of success of the trial. Anifrolumab has also been investigated for the treatment of Scleroderma. Anifrolumab was granted FDA approval on 30 July 2021. |
| CAS Number: | 1326232-46-5 |
| Molecular Weight: | |
| DrugBank Indication: | Anifrolumab is indicated in the treatment of adults with moderate to severe systemic lupus erythematosus. |
| DrugBank Pharmacology: | Anifrolumab is a type 1 interferon receptor (IFNAR) inhibiting IgG1κ monoclonal antibody indicated in the treatment of adults with moderate to severe systemic lupus erythematosus. It has a long duration of action as it is given every 4 weeks. Patients should be counselled regarding the risks of serious infections, hypersensitivity reactions, and malignancies. |
| DrugBank MoA: | Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple systems in the body. SLE may manifest as a rash on the skin, and can progress to life-threatening autoimmune reactions in the kidney or nervous system. Type 1 interferon pathway activation has been identified as a mediator of pathogenesis in SLE, and the level of type 1 interferon expression is correlated with severity of SLE. Activation of the type 1 interferon receptor (INFAR1) by interferons alpha, beta, epsilon, kappa, and omega lead to stimulation of gene transcription. Activation of INFAR1 and INFAR2 lead to phosphorylation of STAT1 and STAT2, which are translocated with interferon regulatory factor 9 (IRF9) to the cell nucleus to activate the interferon-stimulated response element (ISRE). Activation of ISRE leads to the expression of many proinflammatory and immunomodulatory proteins, as well as the activation of a positive feedback loop that produces more type 1 interferons. Interferon alpha stimulates monocytes to mature into myeloid dendritic cells that express self antigens. CD4+ and CD8+ T-cells, as well as B cells, that are autoreactive will respond to the self antigens and induce inflammmation and apoptosis in cells. This self-reactive immune response damages otherwise healthy tissue throughout the body. Anifrolumab is an immunoglobulin gamma 1 kappa (IgG1κ) monoclonal antibody that selectively binds to subunit 1 of INFAR1. The binding of anifrolumab to IFNAR1 inhibits the activity of the receptor, decreasing downstream signalling and gene transcription of inflammatory mediators. The Fc region of anifrolumab carries the triple mutaion L234F/L235E/P331S to prevent binding of the Fc region of the antibody to cell surface Fc receptors. In a phase IIb clinical trial, the primary endpoint was reached by 34.3% of patients in the 300 mg treatment group, 28.8% of patients in the 1000 mg treatment group, and 17.6% of patients in the placebo group. Patients with higher interferon-stimulated gene transcription at baseline showed a greater response to treatment. |
| Targets: | Interferon alpha/beta receptor 1 inhibitor |
| Inclusion Criteria: | Therapeutic strategy associated |
| Strategy ID | Strategy | Synonyms | Related Targets | Related Drugs | |
|---|---|---|---|---|---|
| S13 | Anti-apoptosis | hepatocyte apoptosis; hepatic autophagy; apoptosis | Pan-caspase inhibitor | Emricasan | Details |
| S05 | Anti-inflammatory | inflammatory | Bile acid; TNF-a inhibitor; Dual PPAR-α and -δ agonists; Toll-Like Receptor; (TLR)-4 antagonist; Caspase inhibitor; ASK-1 inhibitor | Ursodeoxycholic Acid; Pentoxifylline; Elafibranor; JKB-121; Emricasan; Selonsertib; | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class |
|---|