iscalimab (CFZ533) / Novartis - LARVOL DELTA

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

TWINSS Extn: Study of Safety and Tolerability of CFZ533 in Patients With Sjögren's Syndrome (clinicaltrials.gov) - P2 | N=206 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Immunology • Sjogren's Syndrome

Study of Efficacy and Safety of Investigational Treatments in Patients With Moderate to Severe Hidradenitis Suppurativa (clinicaltrials.gov) - P2 | N=248 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Dermatology • Hidradenitis Suppurativa • Immunology

Iscalimab Combined With Transient Tesidolumab Prolongs Survival in Pig-to-Rhesus Monkey Renal Xenografts. (PubMed, Xenotransplantation) - "It may be reasonable to evaluate an iscalimab-based immunosuppressive regimen in clinical renal xenotransplantation."

Journal • Preclinical • Transplantation • CD40LG • CD55

Safety and efficacy of subcutaneous iscalimab (CFZ533) in two distinct populations of patients with Sjögren's disease (TWINSS): week 24 results of a randomised, double-blind, placebo-controlled, phase 2b dose-ranging study. (PubMed, Lancet) - P2 | "The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials."

Journal • P2b data • Dry Eye Disease • Fatigue • Immunology • Ophthalmology • Rheumatology • Sjogren's Syndrome • CD40

CONTRAIL I: Study of Efficacy, Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) of an Anti-CD40 Monoclonal Antibody, CFZ533, in Liver Transplant Recipients With Additional 12-month Follow-up and Long-term Extension (clinicaltrials.gov) - P2 | N=128 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; The study was terminated following less favorable efficacy by Iscalimab (CFZ533) in liver transplant patients compared to tacrolimus.

Trial termination • Hepatology • Immunology • Transplant Rejection • Transplantation

SAFETY AND EFFICACY OF ISCALIMAB IN PATIENTS WITH SJÖGREN'S DISEASE: 48-WEEK RESULTS FROM A RANDOMISED, PLACEBO-CONTROLLED, PHASE 2B DOSE-RANGING TRIAL (EULAR 2024) - "By Wk 48, all iscalimab doses showed further improvements in disease activity outcomes and PROs, corroborating the results seen at Wk 24 in two distinct groups of patients with active SjD. Iscalimab's benefit-risk warrants further evaluation."

Clinical • P2b data • Cardiovascular • Congestive Heart Failure • Dry Eye Disease • Fatigue • Heart Failure • Immunology • Infectious Disease • Ophthalmology • Pneumonia • Respiratory Diseases • Sjogren's Syndrome

CCFZ533X2207: Study of Safety and Efficacy of CFZ533 in Type 1 Diabetes Pediatric and Young Adult Subjects (clinicaltrials.gov) - P2 | N=44 | Completed | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Completed

Trial completion • Diabetes • Metabolic Disorders • Pediatrics • Type 1 Diabetes Mellitus

Focus on Sjögren's syndrome - Diagnosis and treatment (PubMed, Dtsch Med Wochenschr) - "A particularly large number of therapeutic approaches are dedicated to the B cell: Rituximab and Belimumab have been included in the EULAR recommendations for serious manifestations and Ianalumab has a promising effect. Another focus of current research is the inhibition of co-stimulation between immune cells. After recent disappointing results for Abatacept, clinical trials show promising effects on Iscalimab and Dazodalibep."

Biomarker • Journal • Review • Cardiovascular • Hematological Malignancies • Immunology • Inflammatory Arthritis • Lupus • Lymphoma • Oncology • Rheumatoid Arthritis • Rheumatology • Sjogren's Syndrome • Systemic Lupus Erythematosus

The Immune Landscape in Renal Allograft Rejection is Shaped by Immunosuppression Modality (ATC 2024) - "As different mIS regimens can confer differing susceptibility to later development of antibody-mediated rejection, we examined the effects of mIS on non-T cells (i.e., B cells and myeloid cells) during ACR.* scRNAseq was performed on biopsies of 10 patients undergoing renal allograft rejection (RAR) under 3 maintenance IS therapies (tacrolimus [CNI], belatacept [CTLA4-Ig], and iscalimab [anti-CD40 mAb]). Co-stimulatory blockade mIS regimens reduce the recruitment/accrual of specific populations of activated B cells to kidney allografts compared to tacrolimus mIS."

Antibody-mediated Rejection • Transplant Rejection

Study of Efficacy and Safety of Investigational Treatments in Patients With Moderate to Severe Hidradenitis Suppurativa (clinicaltrials.gov) - P2 | N=245 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Oct 2026 ➔ Nov 2024

Trial primary completion date • Dermatology • Hidradenitis Suppurativa • Immunology