sifalimumab (MDX-1103) / AstraZeneca - LARVOL DELTA

An Integrative Mechanistic Model of Type 1 IFN-Mediated Inflammation in Systemic Lupus Erythematosus. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Results of the global sensitivity analysis revealed baseline IFNGS, IFNα, and IFNα fraction as key factors affecting treatment benefit the most. In terms of maximum IFNGS reduction, anifrolumab showed superior potential compared to sifalimumab, daxdilimab, and litifilimab (ΔIFNGS~25%), which was further enhanced in patients with high baseline IFNGS or IFNα (ΔIFNGS~50%-60%)."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • IFNA1

Type I interferon pathway in pediatric systemic lupus erythematosus. (PubMed, World J Pediatr) - "This review presents an overview of the IFN-I pathway in pediatric SLE. Understanding the intricate relationship between IFN-I and pediatric SLE may help to identify potential diagnostic markers and targeted therapies, paving the way for improved patient care and outcomes."

IO biomarker • Journal • Review • Immunology • Inflammatory Arthritis • Interferonopathies • Lupus • Pediatrics • Systemic Lupus Erythematosus • CGAS • IFNA1 • LGALS9 • STING • TLR9 • TYK2

Targeting Type I IFN in SLE and lupus nephritis (LUPUS 2024) - "Although rontalizumab and sifalimumab, the first two monoclonal antibodies directed against interferon alpha to be evaluated in clinical trials, yielded negative and modest clinical trial results, respectively, other pursuits were undertaken that proved more fruitful. The anifrolumab program reaffirmed the clinical significance of type I IFN in SLE and boosted confidence that other approaches to inhibit type I IFN would prove efficacious. This presentation will review various strategies being pursued in order to block the interferon pathway in SLE and lupus nephritis."

Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • IFNA1 • IFNAR2

Model-based meta-analysis using latent variable modeling to set benchmarks for new treatments of systemic lupus erythematosus. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Continuous dose-effect relationships using a maximum effect model were included for anifrolumab, belimumab, CC-220 (iberdomide), epratuzumab, lulizumab pegol, and sifalimumab, whereas the remaining treatments were modeled as discrete dose effects. The final MBMA model was then used to benchmark these compounds with respect to the maximal efficacy on the latent variable compared to the placebo. This MBMA illustrates the application of latent variable models in understanding the trajectories of composite end points in chronic diseases and should enable model-informed development of new investigational agents in SLE."

Journal • Retrospective data • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Safety and efficacy of biological agents in the treatment of Systemic Lupus Erythematosus (SLE). (PubMed, BMC Rheumatol) - "Multiple biologic agents are shown in high quality studies to have a significant therapeutic impact on outcomes in SLE."

Journal • Cutaneous Lupus Erythematosus • Herpes Zoster • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • Varicella Zoster • IL12A

Advances in natural products and antibody drugs for SLE: new therapeutic ideas. (PubMed, Front Pharmacol) - "This review discusses the current experience including B-cell targeted drugs (belimumab, tabalumab, blisibimod, atacicept, rituximab, ofatumumab, ocrelizumab, obexelimab, and epratuzumab), T-cell targeted drugs (abatacept, dapirolizumab, and inhibitor of syk and CaMKIV), cytokines targeted drugs (anifrolumab and sifalimumab), and natural products (curcumin, oleuropein, punicalagin, sulforaphane, icariin, apigenin, and resveratrol). The aim of this paper is to combine the existing in vitro and in vivo models and clinical research results to summarize the efficacy and mechanism of natural drugs and targeted drugs in SLE for the reference and consideration of researchers."

Journal • Review • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • SYK

Type I interferon targeted therapy (LUPUS-KCR 2023) - "Early trials with the IFN antagonists rontelizumab and sifalimumab were not convincing, but a large clinical development program for the IFN-receptor antagonist anifrolumab led to its approval by regulatory authorities including the FDA and EMA...Litifilimab (anti-BDCA2 monoclonal antibody) downregulates the production of type I IFN by plasmacytoid dendritic cells and showed promising phase 2 results in both systemic and cutaneous lupus. The TYK2 inhibitor deucravacitinib targets IFN-mediated signalling (and other pathways) and showed promising results in a phase 2 trial in SLE. Phase 3 trials are ongoing with both these agents. In summary, interferon antagonism appears to be a rational, specific and promising approach in the therapy of SLE and other IFN-related diseases."

Cutaneous Lupus Erythematosus • Glomerulonephritis • Herpes Zoster • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Varicella Zoster • TYK2

Current and new targets for treating myositis. (PubMed, Curr Opin Pharmacol) - "In the largest clinical trial to date, rituximab was studied in adult and juvenile myositis, but the primary outcome was not met despite 83 percent of subjects with refractory myositis meeting the definition of improvement. The U.S. Food and Drug Administration (FDA) has recently granted approval to Octagam 10% immune globulin intravenous (IVIg), for the treatment of adult dermatomyositis based on impressive results from a double-blind placebo-controlled trial...Further, anti-IL6 therapy cannot be recommended as a recent trial of tocilizumab failed to reach its primary endpoint. Further studies are needed to assess the role of newer therapies such as abatacept (inhibition of T cell co-stimulation), sifalimumab (anti-IFNα), Janus kinase [JAK] inhibitors, apremilast (phosphodiesterase 4 inhibitor), and KZR-616 (selective inhibitor of the immunoproteasome) given their biological plausibility and encouraging recent small-case series results. The future of IIM therapy will..."

Clinical • Journal • Review • Dermatomyositis • Immune Modulation • Immunology • Inflammation • Myositis • Oncology • IFNA1

Antibody Therapies in Autoimmune Inflammatory Myopathies: Promising Treatment Options. (PubMed, Neurotherapeutics) - "The use of therapeutical antibodies in myositis has been examined in various clinical studies, several of them randomized controlled ones: Depletion of B-cells by rituximab has been established as treatment of refractory myositis...Negative study results were reported in randomized trials with infliximab, sifalimumab and bimagrumab. Studies on basiliximab and eculizumab are currently underway, and are expected to yield results in a couple of years. Despite some promising results of clinical studies with antibody therapy in myositis, further research is crucial to optimize the treatment for this debilitating disease and to find treatment alternatives for treatment-refractory patients."

Journal • Review • Dermatomyositis • Immunology • Inflammation • Myositis • Rare Diseases

Inflammatory myopathies: Shedding light on promising agents and combination therapies in clinical trials. (PubMed, Expert Opin Investig Drugs) - "Current studies in most myositis subtypes have shown positive effects of novel biologicals such as abatacept, sifalimumab, JAK-Inhibitors as well as known agents such as rituximab, but further studies are needed to confirm these observations. In inclusion body myositis, the eagerly awaited recent therapeutic trials have missed their primary endpoints, except for the phase 2 study with rapamycin, which has demonstrated significant improvements in secondary endpoints. Future trials will also need to focus on combination therapies of multiple immunomodulatory agents."

Clinical • Combination therapy • Journal • Dermatomyositis • Immune Modulation • Immunology • Inflammation • Myositis • Rare Diseases

An Update on the Management of Childhood-Onset Systemic Lupus Erythematosus. (PubMed, Paediatr Drugs) - "Antimalarials and glucocorticoids are still the most common drugs used to treat cSLE, and hydroxychloroquine is recommended for nearly all cSLE patients...Mycophenolate mofetil or intravenous cyclophosphamide is suggested as induction therapy for lupus nephritis classes III and IV. Calcineurin inhibitors (cyclosporine, tacrolimus, voclosporin) appear to be another good option for cSLE patients with lupus nephritis. Regarding B-cell-targeting biologic agents, rituximab may be used for refractory lupus nephritis patients in combination with another DMARD, and belimumab was recently approved by the US Food and Drug Administration for cSLE treatment in children aged > 5 years. New therapies targeting CD20, such as atacicept and telitacicept, seem to be promising drugs for SLE patients. Anti-interferon therapies (sifalimumab and anifrolumab) have shown beneficial results in phase II randomized control trials in adult SLE patients, as have some Janus kinase inhibitors, and..."

Clinical • Journal • Complement-mediated Rare Disorders • Glomerulonephritis • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Pediatrics • Renal Disease • Rheumatoid Arthritis • Systemic Lupus Erythematosus

S95021, a novel selective and pan-neutralizing anti interferon alpha (IFN-α) monoclonal antibody as a candidate treatment for selected autoimmune rheumatic diseases. (PubMed, J Transl Autoimmun) - "S95021 was IFN-α-selective and exhibited superior potency and broader neutralization profile when compared with the benchmark anti-IFN-α mAbs rontalizumab and sifalimumab. Together, our results show that S95021 is a new potent, selective and pan IFN-α-neutralizing mAb. It is currently further evaluated as a valid therapeutic candidate in selected autoimmune diseases in which the IFN-α pro-inflammatory pathway is dysregulated."

Journal • Immunology • Inflammatory Arthritis • Lupus • Rheumatology • Sjogren's Syndrome • Systemic Lupus Erythematosus • STAT1

[VIRTUAL] Efficacy of Biological Agents for the Management of Systemic Lupus Erythematosus: A Systematic Review and Network Meta-Analysis (CRA-AHPA 2021) - "These 20 RCTs investigated the following biologics: belimumab, anifrolumab, ustekinumab, atacicept, baricitinib, blisibimod, epratuzumab, IL-2, lupuzor, PF-04236921, rontalizumab, sifalimumab, and tabalumab... The NMA identified that belimumab, anifrolumab and ustekinumab demonstrated greater response in comparison to placebo, when measured using SRI. This systematic review identified that there was heterogeneity in the outcome measures and endpoints used. In the future, the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach will be applied to rate the quality of the evidence, and to gain insight into methodological pitfalls that could have negatively altered the results of RCTs."

Retrospective data • Review • Complement-mediated Rare Disorders • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Systemic Lupus Erythematosus • IL2

Safety and tolerability of sifalimumab, an anti-interferon-α monoclonal antibody, in Japanese patients with systemic lupus erythematosus: a multicentre, phase 2, open-label study. (PubMed, Mod Rheumatol) - "Sifalimumab was well tolerated in Japanese patients with SLE."

Clinical • Journal • P2 data • Immunology • Lupus • Systemic Lupus Erythematosus

AstraZeneca: Q2 2014 Results (AstraZeneca) - Anticipated data from P2b trial for SLE at ACR (Nov 14-19, 2014)

Anticipated P2b data • Immunology • Lupus

Intravenous pharmacokinetics and immunogenicity of sifalimumab, an anti-interferon-α monoclonal antibody, in systemic lupus erythematosus (EULAR 2011) - P1b, N=160; Incidence of anti-sifalimumab antibodies was 19.7% in sifalimumab treated pts PBO 2.2% in PBO; Anti-sifalimumab antibody titers were low & did not impact sifalimumab PK

P1b data • Immunology

AstraZeneca: Investor Relations Presentation (AstraZeneca) - "Sifalimumab (lupus): Significant improvement in SLE responder index and organ specific measurements specific measurements"

P2 data • Immunology • Lupus

AstraZeneca: Q1 2014 Results (AstraZeneca) - Anticipated initiation of P3 trial for systemic lupus erythematosus in 2015

Anticipated new P3 trial • Immunology • Lupus

Medimmune presents promising new data in systemic lupus at American College of Rheumatology meeting (Medimmune Press Release) - P2b, N=431; NCT01283139; Sponsor: MedImmune; "The results show that the percentage of patients achieving improvement as measured by the SLE Responder Index (SRI-4) at week 52 was significantly higher for sifalimumab at all doses versus placebo plus standard of care (placebo/SOC, 45.4%; 200 mg, 58.3%; 600 mg, 56.5%; 1200 mg, 59.8%)...MedImmune also shared results from two open-label Phase II studies, one with sifalimumab and one with anifrolumab..."

P2 data • Immunology • Lupus

AZ: Investor Day (AstraZeneca) - Anticipated data from P2 trial for SLE in 2013; Anticipated initiation of P3 trial for SLE in 2014

Anticipated new P3 trial • Anticipated P2 data • Immunology • Lupus

AstraZeneca to showcase inflammation/ autoimmunity pipeline at ACR (The Pharma Letter) - "Positive results from the Phase IIb study evaluating the safety and efficacy of sifalimumab in patients with moderate-to-severe lupus will be presented in a late-breaking oral presentation. In addition, pharmacokinetic and pharmacodynamic data will be presented on both sifalimumab and anifrolumab from two trials of adult Japanese patients with lupus."

Anticipated P2 data • Anticipated PK/PD data • Immunology • Lupus

AstraZeneca announces MedImmune’s mavrilimumab and sifalimumab both met primary endpoints in phase IIb studies (AstraZeneca Press Release) - P2, N=431; NCT01283139; Sponsor: MedImmune; "MedImmune also announced top-line results from the Phase II study of sifalimumab (MEDI-545), a novel monoclonal antibody being investigated as a treatment for patients with moderate/severe systemic lupus erythematosus (SLE or lupus). The study met its primary endpoint of percentage of subjects that responded by the SLE Responder Index (SRI-4) at Day 365. Clinically important improvements in organ-specific outcome measures (joint, skin) and patient reported outcomes were also observed."; Anticipated additional study results at a future medical conference later this year.

Anticipated conference • Anticipated P2 data • P2 data • Immunology • Lupus

AstraZeneca: Q1 2014 Results (AstraZeneca) - Anticipated top-line data from P2b trial for systemic lupus erythematosus in Q3 2014

Anticipated P2 data • Immunology • Lupus

Sifalimumab, a human anti–interferon-α monoclonal antibody, in systemic lupus erythematosus: A phase I randomized, controlled, dose-escalation study (Arthritis Rheum) - P1, N=161; Sponsor: MedImmune; NCT00482989; "In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%...No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed...The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE."

P1 data • Immunology • Lupus

A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients (Ann Rheum Dis) - P1b, N=51; Sponsor: MedImmune; NCT00533091; "Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle."

P1 data • Immunology