iscalimab (CFZ533) / Novartis - LARVOL DELTA

The Sjögren's Tool for Assessing Response (STAR) demonstrates its ability to accurately detect treatment efficacy in 17 recent RCTs in Sjögren's disease (ACR Convergence 2026) - P1/2, P2, P2/3, P3 | " The following data were used to assess the performance of 20 STAR candidate options: Data from 9 clinical trials used for STAR development: abatacept (NCT02915159), leflunomide + hydroxychloroquine (REPURPSS-I, EudraCT 2020-001933-11), rituximab (TEARS NCT0074094, TRACTISS ISRCTN65360827), hydroxychloroquine (JOQUER NCT00632866), tocilizumab (NCT01782235), baminercept (NCT01552681), and phase II trials of iscalimab (NCT02291029) and ianalumab (NCT02962895). Data from 7 independent clinical trial datasets (external validation set): belimumab ± rituximab (NCT02631538), abatacept (NCT02915159), anti-IL-7 therapy (NCT04605978), remibrutinib (NCT04035668), iscalimab (NCT03905525, cohorts 1 and 2), leflunomide + hydroxychloroquine (EudraCT 2020-001933-11), and dazodalibep (NCT04129164)... This large number of new trials provided a large amount of data for informing the selection of the final STAR responder index. The STAR 3AV1 where response rely on..."

Clinical • Sjogren's Syndrome • IL7

Immunosuppressive and immunomodulatory therapies in Sjögren's disease: current landscape and future perspectives. (PubMed, Expert Opin Pharmacother) - "CAR-T cell therapy application in refractory SjD patients currently represents an emerging, strictly experimental approach requiring rigorous evaluation of safety and long-term feasibility. Ultimately, identifying the most effective therapeutic agents will likely require discovering and implementing biomarkers tailored to specific biological endotypes."

IO biomarker • Journal • Review • Immunology • Sjogren's Syndrome • CD40LG • CTLA4

From Molecular Pathophysiology to Clinical Trial Design in Sjögren's Disease: A Three-Axis Framework. (PubMed, Int J Mol Sci) - "Recent positive trials-phase III for ianalumab in NEPTUNUS-1/2, phase 2b for iscalimab in TWINSS, phase 2 for nipocalimab in DAHLIAS, and phase 2 for dazodalibep in a phenotype-defined symptom-dominant cohort-illustrate that meaningful clinical benefit becomes detectable once stratification is aligned to biology. By integrating molecular endotypes, validated biomarkers, composite endpoints, and phenotype-matched therapies onto a single explicit architecture, SjD shifts from a recurring example of translational failure to a model for precision medicine in heterogeneous autoimmune disease. The central message is that SjD may be less intrinsically treatment-resistant than it has historically been treatment-mistargeted."

Biomarker • Journal • Review • Immunology • Rheumatology • Sjogren's Syndrome

Limited efficacy of a therapeutic anti-CD40 monoclonal antibody to inhibit activated CD4 T cell autoimmunity in vitro. (PubMed, PLoS One) - "The CD40 blockade also did not affect the induction of proliferation of naïve alloreactive CD4 T cells, by dendritic cells. Based on our in vitro data pointing to minimal inhibition of T cells by CD40 blockade, we propose that iscalimab may not suffice to accomplish durable benefit as intervention strategy to treat type 1 diabetes or other T cell mediated diseases."

Journal • Preclinical • Diabetes • Immunology • Metabolic Disorders • Transplantation • Type 1 Diabetes Mellitus • CD40LG

Advances and unmet needs in the management of proliferative lupus nephritis: evidence, guidelines, and emerging therapies. (PubMed, Kidney Res Clin Pract) - "Although mycophenolate-based regimens and cyclophosphamide remain standard induction therapies, up to one-third of patients have refractory disease, and many fail to achieve a complete renal response, as demonstrated in the ASPREVA, AURORA, and BLISSLN trials...Belimumab improves composite and complete renal response rates when added to standard therapy and reduces renal events, particularly in patients with proliferative histology. Voclosporin, a novel calcineurin inhibitor with predictable pharmacokinetics, increases complete renal response rates and rapidly reduces proteinuria in patients with preserved kidney function...Obinutuzumab, a type II anti-CD20 monoclonal antibody, demonstrated higher complete renal response rates than placebo in a phase 3 trial, albeit with increased serious infections. Anifrolumab, which targets type I interferon signaling, has shown favorable trends in reducing proteinuria and systemic disease activity in early lupus nephritis studies and..."

IO biomarker • Journal • Glomerulonephritis • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Systemic Lupus Erythematosus • CD40

Iscalimab (CFZ533) in patients with Sjögren’s disease (TWINSS): histopathological and transcriptomic findings from a salivary gland biopsy sub-study (EULAR 2026) - "Conclusions The results suggest that CD40 inhibition might impact inflammation in salivary glands, evidenced by decreased focus scores and reduced CD45+ immune cell infiltration. These tissue-level findings are in line with reduced transcription levels of CD40 and genes related to inflammatory cells."

Biopsy • Clinical • IO biomarker • Dry Eye Disease • Inflammation • Ophthalmology • Sjogren's Syndrome • BCL6 • CD20 • CD21 • CD40LG • CD80 • CXCL13 • ICAM1 • PTPRC • SDC1

The Sjögren’s Tool for Assessing Response (STAR) demonstrates its ability to accurately detect treatment efficacy in 15 recent RCTs in Sjögren’s disease (EULAR 2026) - P2, P3 | "Methods Data from 15 trials used for STAR development (Abatacept (ASAP-III), leflunomide + hydroxychloroquine (REPURP-SS) and rituximab (TEARS and TRACTISS), the iscalimab and ianalumab phase 2 trials, Baminercept, hydroxychloroquine (JOQUER), tocilizumab (ETAP) and 6 other independent clinical trials (GSK (NCT02631538), Belimumab + Rituximab, Belimumab, Rituximab versus placebo and BMS Abatacept (NCT02915159 presentation (Servier, anti-IL7 NCT04605978; Novartis : Remibrutinib (NCT04035668) and Iscalimab (), leflunomide + hydroxychloroquine (REPURP-SS). Data from Dazodalibep (Amgen, CD40L antagonist NCT04129164) to be present during full analysis)...Conclusions In this analysis based on 15 trials, the STAR candidate, and some alternatives options, appears to detect treatment response accurately, with a high sensitivity to change for treatments showing a beneficial effect. Additionally, it exhibits specificity to change by not falsely detecting improvement in..."

Clinical • Sjogren's Syndrome • CD40LG • IL7

Efficacy and safety of pharmacological treatment for Sjögren's disease: a network meta-analysis. (PubMed, Z Rheumatol) - "Compared to PBO, iscalimab, dazodalibep, iguratimod, remibrutinib, leflunomide + hydroxychloroquine, ianalumab, and filgotinib significantly reduced the ESSDAI score, with no distinctions in the ESSPRI score. No significant differences in safety profiles were fond between any drugs and PBO."

Journal • Retrospective data • Review • Dry Eye Disease • Immunology • Ophthalmology • Rheumatology • Sjogren's Syndrome • Xerostomia

Pathophysiological aspects of primary Sjögren's disease : From epithelial activation to systemic autoimmunity (PubMed, Z Rheumatol) - "The pathophysiology of SjD is a multistage process in which the early activation of the salivary epithelium and subsequent activation of the innate immune system with IFN play a crucial role in its initiation. This is followed by activation of the adaptive immune system with a focus on T‑B cell interaction and pathological B cell activation. The chronic inflammation in SjD can be understood as positive feedback from the activation of the innate and adaptive immune systems, which innovative therapeutic approaches aim to interrupt. These comprise TLR and IFN blockade, inhibition of T‑B cell interaction via CD154/CD40 blockade (e.g., dazodalibep, iscalimab) or B cell depletion strategies including. anti-BAFF‑R and anti-CD19 CAR-T cells."

Journal • Review • Immunology • Inflammation • Sjogren's Syndrome • CD40 • CD40LG

Effectiveness of biological drugs in the treatment of xerostomia and salivary hypofunction in patients with Sjögren disease. (PubMed, J Am Dent Assoc) - "RTX, iscalimab, and IFN-α have potential benefits in management of salivary gland dysfunction in SjD. Adequate methodological trials are needed to clarify the role of these agents in SjD. The research protocol was planned and registered with PROSPERO, an international systematic review registry (CRD42024596176), and it was not modified throughout the study."

Clinical • Journal • Review • Dental Disorders • Sjogren's Syndrome • Xerostomia • IFNA1

A Phase 2 (2a) Randomized Trial of Iscalimab in Adolescents and Young Adults with New-Onset Type 1 Diabetes. (PubMed, Diabetes Technol Ther) - "The sample size limits interpretation of efficacy results. CD40:CD154 inhibition warrants further investigation in T1DM."

Journal • P2 data • Diabetes • Hematological Disorders • Hypoglycemia • Immune Modulation • Immunology • Infectious Disease • Metabolic Disorders • Musculoskeletal Diseases • Nephrology • Neutropenia • Novel Coronavirus Disease • Orthopedics • Type 1 Diabetes Mellitus • CD40LG

Co-Stimulatory Blockade Prevents Intragraft Accrual of Class-Switched, Activated B Cells Despite Failing to Prevent T-Cell Mediated Rejection. (PubMed, bioRxiv) - "Here, using single cell RNA sequencing (scRNAseq), we investigated non-CD8 + immune cells during T-cell-mediated rejection (TCMR) under different maintenance immunosuppression (mIS) regimens: tacrolimus, and co-stimulatory blockade (CoB) with belatacept (CTLA4-Ig) or iscalimab (anti-CD40). Notably, cell-cell communication analysis indicated Th17 and Tph cell interactions with B CS cells in tacrolimus, but not CoB, samples. Thus, although failing to prevent TCMR, CoB mIS modulates the accrual of CD4 + T cells and inhibits the intragraft accrual of B CS cells, possibly reflective of clinical observations of less chronic antibody-mediated rejection under CoB mIS."

IO biomarker • Journal • Antibody-mediated Rejection • Transplant Rejection • CD8 • CXCL13 • FOXP3

The Sjögren's Tool for Assessing Response (STAR) demonstrates its ability to accurately detect treatment efficacy in 11 recent RCTs in Sjögren's disease (ACR Convergence 2025) - P2, P3 | "We conduscted this study to evaluate the performance of STAR in previously completed clinical trials shared within the NECESSITY consortium. Data from 9 trials used for STAR development (Abatacept (ASAP-III), leflunomide+hydroxychloroquine (REPURP-SS) and rituximab (TEARS and TRACTISS), the iscalimab and ianalumab phase 2 trials, Baminercept, hydroxychloroquine (JOQUER), tocilizumab (ETAP)) and two other independent clinical trials (GSK (NCT02631538), Belimumab + Rituximab, Belimumab, Rituximab versus placebo and BMS Abatacept (NCT02915159). In this analysis based on 11 trials, the STAR appears to detect treatment response accurately, with a high sensitivity to change for treatments showing a beneficial effect. Additionally, it exhibits specificity to change by not falsely detecting improvement in negative trials."

Clinical • Sjogren's Syndrome

Study the Efficacy and Safety of VAY736 and CFZ533 in SLE Patients (clinicaltrials.gov) - P2 | N=107 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed | Trial completion date: Apr 2026 ➔ Apr 2025

Trial completion • Trial completion date • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Efficacy, pharmacokinetics and safety of iscalimab (CFZ533) in patients with proliferative lupus nephritis: a randomised, double-blind, placebo-controlled, phase II study. (PubMed, RMD Open) - P2 | "Iscalimab showed a significant improvement in proteinuria (UPCR) in patients with active LN. Iscalimab was generally well tolerated with the exception of a few severe infections and one case of macrophage-activation syndrome in immunosuppressed and comorbid patients."

Journal • P2 data • PK/PD data • Glomerulonephritis • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Systemic Lupus Erythematosus

Co-Stimulatory Blockade Prevents Intragraft Accrual of Class-Switched, Activated B Cells and Th17 T Cells and Promotes Accrual of Tregs (WTC 2025) - "To gain insight into the effects of CsB on non-CD8+ T cells during ACR, we analyzed single cell RNA sequencing (scRNAseq) data on biopsies from patients experiencing ACR under tacrolimus, belatacept, or anti-CD40 (iscalimab) based maintenance immunosuppression (mIS).* Kidney allograft biopsies from 10 patients experiencing ACR under distinct mIS (tacrolimus, N=4; belatacept, N=3; iscalimab, N=3) were obtained, subjected to cold-active protease digestion and scRNAseq performed using the 10x Chromium 5' platform with TCR sequencing. Our data show that CsB prevented accrual of intragraft csB cells and altered the landscape of the CD4+ T cell compartment, consistent with known effects of CsB, including the long-term reduction in DSA and ABMR in patients under CsB. . Interestingly, these data highlight the dynamic nature of rejection and that despite the reduction of multiple pathogenic subsets (Th17, cs B cells, Tph) and emergence of potentially tolerogenic subsets..."

IO biomarker • CD8 • CXCL13

Iscalimab in Adolescents and Young Adults with New-Onset Type 1 Diabetes (ADA 2025) - "CFZ533 was generally safe and well tolerated. During treatment 5 serious adverse events (AEs) occurred in iscalimab (large intestine infection, urinary tract infection, traumatic fracture, diabetic metabolic decompensation, and hypoglycemia (3.4% each) and 1 in placebo (mastoiditis (6.7%)). The most common AEs were hypoglycemia, nasopharyngitis, injection site reaction, COVID-19 and neutropenia."

Clinical • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus • CD40LG

Iscalimab 600 mg: justified or excessive? (PubMed, Lancet) - No abstract available

Journal

Iscalimab 600 mg: justified or excessive? - Authors' reply. (PubMed, Lancet) - No abstract available

Journal

Targeted immunotherapies for Graves' thyroidal & orbital diseases. (PubMed, Front Immunol) - "They include rituximab, an anti-CD20 monoclonal antibody which causes rapid B cell depletion; ATX-GD-59, an antigen specific immunotherapy which restores immune tolerance to thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 co-stimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor blocking monoclonal antibody...Both tocilizumab (anti-interleukin 6 receptor monoclonal antibody) and sirolimus (mammalian target of rapamycin inhibitor) showed promise in glucocorticoid resistant active disease. Teprotumumab, an anti-insulin-like growth factor-1 receptor monoclonal antibody, demonstrated remarkable all-round efficacy across a wide disease spectrum. Linsitinib, a dual small molecule inhibitor of insulin-like growth factor-1 receptor and insulin receptor, displayed significant proptosis reduction in its phase 2b/3 study. Finally, Batoclimab, an anti-neonatal fragment crystallizable receptor monoclonal antibody,..."

Journal • Review • Endocrine Disorders • Grave’s Disease • Immunology • Ocular Inflammation • Ophthalmology • Optic Neuritis • Pain • Thyroid Eye Disease • CD40LG • IL6R • IR

Costimulation blockade: the next generation. (PubMed, Curr Opin Organ Transplant) - "The focus in transplantation is shifting toward safer, long-term therapies with greater accessibility. Investigational agents with subcutaneous delivery methods could overcome logistical challenges, improve adherence, and redefine posttransplant care. These advancements in costimulation blockade may enhance long-term graft survival and transform the management of KT recipients."

Journal • Cardiovascular • Transplantation • CD40LG

Infections in Sjögren's disease: a clinical concern or not? (PubMed, Clin Exp Rheumatol) - "While biologic therapies, including predominantly rituximab and belimumab have become increasingly utilised, they carry inherent risks of infections due to their immunosuppressive effects. Emerging therapies, such as ianalumab, iscalimab, dazodalibep, and remibrutinib, show efficacy in reducing disease activity but also present infection risks, with reports of upper respiratory infections and serious cases, including pneumonia and COVID-19. By exploring these infection-related challenges, this review underscores the importance of understanding the infection-autoimmunity relationship to improve outcomes for patients with SjD and similar autoimmune conditions."

Journal • Review • Hematological Malignancies • Immunology • Infectious Disease • Lymphoma • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • Sjogren's Syndrome • Urology

New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review. (PubMed, Ther Drug Monit) - "The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents."

Journal • Review • Hepatology • Solid Organ Transplantation • Transplantation • CD40LG • CD80 • TNFSF4

Associations Between Protein Quantitative Trait Loci and Risk of Primary Sjögren's Syndrome: A Mendelian Randomization Study (ACR Convergence 2024) - "We provided genetic evidence further elucidating the complexity of primary Sjögren's disease pathogenesis. Additionally, we suggested a genetic causal link between CD40 and primary Sjögren's disease – supporting the continued investigation of anti-CD40 therapy, such as iscalimab, as a novel treatment for this condition."

IO biomarker • Immunology • Sjogren's Syndrome

A Post-hoc Analysis of Two Phase 2 Randomized Controlled Trials in Patients with Active Sjogren's Disease Exploring the Novel Composite Endpoint Sjögren's Tool for Assessing Response (STAR) (ACR Convergence 2024) - P2 | "Background/Purpose: Two randomized controlled phase 2 trials in patients with active Sjogren's disease (SjD) were recently completed, the LOUiSSe trial assessing the Bruton Tyrosine kinase inhibitor remibrutinib (LOU064; NCT04035668; Dörner et al (1), and the TwinSS trial assessing the fully human monoclonal antibody against CD40, iscalimab (CFZ533; NCT03905525). Our post-hoc exploratory analysis of two recent interventional phase 2 randomized controlled trials suggests utility of STAR as a single composite outcome measure for SjD studies. Encompassing all key disease features, STAR appears to perform well in major subsets of patients with SjD including a subgroup with high symptom burden and low systemic activity. STAR yields a comparatively low placebo response rate, and good differentiation between active and control arms."

Clinical • P2 data • Retrospective data • Fatigue • Immunology • Sjogren's Syndrome • CD40