clazakizumab (CSL300) / CSL Behring, Lundbeck - LARVOL DELTA

PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study (clinicaltrials.gov) - P2 | N=395 | Completed | Sponsor: University of North Carolina, Chapel Hill | Active, not recruiting ➔ Completed | Trial completion date: Dec 2024 ➔ Mar 2025

Trial completion • Trial completion date • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Targeting IL-6 in antibody-mediated kidney transplant rejection. (PubMed, Clin Kidney J) - "Additionally, the anti-IL-6 receptor antibody tocilizumab and the anti-IL-6 antibody clazakizumab have been studied for the treatment of naïve as well as resistant antibody-mediated kidney allograft rejection with mixed results in observational studies and early clinical development...Investigator-initiated clinical development continues in a smaller phase 3 trial testing tocilizumab (INTERCEPT). In this viewpoint article, we evaluate the pathophysiology of IL-6 in antibody-mediated kidney allograft rejection along with the current status of the clinical development of IL-6 targeting therapies for antibody-mediated kidney allograft rejection episodes within the wider frame of IL-6 targeting therapies in kidney failure that are considered the major causes of graft loss in kidney transplantation."

Journal • Review • Antibody-mediated Rejection • Hematological Disorders • Immunology • Inflammation • Transplant Rejection • Transplantation • IL6

A Phase II Precision Medicine Trial of Clazakizumab for the Treatment of Severe Asthma (ATS 2025) - No abstract available

Late-breaking abstract • P2 data • Asthma • Immunology • Respiratory Diseases

B6 PRECISION MEDICINE IN SEVERE ASTHMA: LATE-BREAKING RESULTS FROM THE PRECISE TRIAL (ATS 2025) - "Objectives describe new thinking about how to design and interpret biomarker-stratified adaptive platform trialsdescribe new findings about the following interventions targeting new pathways in severe and exacerbation-prone asthma: medium chain triglycerides, cavosonstat, imatinib, Broncho-Vaxom®, and clazakizumablearn how established and new biomarkers can predict asthma severity and response to therapy. The learner can apply this new knowledge in clinical practice to improve the care of severe asthmatics"

Late-breaking abstract • Asthma • Immunology • Respiratory Diseases

Clazakizumab treatment effects on kidney transcriptomes in chronic ABMR (BTS-NHSBT JAC 2025) - No abstract available

Combined Dose-Finding and CV Outcomes Study With CSL300 (Clazakizumab) in Adult Subjects With ESKD Undergoing Dialysis (clinicaltrials.gov) - P2/3 | N=2310 | Recruiting | Sponsor: CSL Behring | Trial completion date: Dec 2028 ➔ Aug 2029 | Trial primary completion date: Dec 2028 ➔ Aug 2029

Trial completion date • Trial primary completion date • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease • CRP

Effects of Clazakizumab on Anemia and Iron Metabolism in Patients with Kidney Failure. (PubMed, J Am Soc Nephrol) - No abstract available

Journal • Anemia • Hematological Disorders • Renal Disease

CTLA-4IG + ANTI-IL-6/IL-6R RESULTS IN LONG-TERM REJECTION-FREE GRAFT SURVIVAL IN HIGHLY-HLA SENSITIZED PATIENTS. . (WRMC 2025) - "Two patients 100% cPRA & +FCMX at tx were desensitized with clazakizumab (anti-IL-6, claza)...Two patients received tocilizumab (anti-IL-6R,) were transitioned to CNI-free regimens at 2 & 11 years post-tx... The combination of CTLA4-Ig + anti-IL-6/IL-6R appears to offer benefits in DSA reduction, prevention of dnDSA and AMR/CMR after >4.5 yrs in HS patients. Importantly, CNI toxicity abated in all patients. Although limited, the reductions in CD8+TEFF/MEM, BMEM, NK, and TFH cells with increasing TREG & BREG cell populations suggest immune modulation vs."

Clinical • Immune Modulation • Immunology • CD8 • IL6R

Network meta-analysis of pharmacological treatment for antibody-mediated rejection after organ transplantation. (PubMed, Front Immunol) - "The results indicated that the increase in eGFR by eculizumab (SUCRA score: 81) appeared to be more promising. The decrease in MFI by bortezomib (SUCRA score: 72.3), rituximab (SUCRA score: 68.2), and clazakizumab (SUCRA score: 67.1) demonstrated better efficacy...Clazakizumab appears to be more effective in reducing infections. https://www.crd.york.ac.uk/prospero/, identifier CRD42024546483."

Clinical • Journal • Retrospective data • Review • Antibody-mediated Rejection • Infectious Disease • Transplantation

Effects of Interleukin-6 Inhibition with Clazakizumab on Anemia and Iron Parameters in Patients with Kidney Failure (KIDNEY WEEK 2024) - "Through anti-IL6 effects, clazakizumab may improve iron utilization and contribute to anemia correction in patients receiving dialysis. Larger and longer-term data from the ongoing Phase 3 study will provide additional insights."

Clinical • Anemia • Cardiovascular • Diabetes • Diabetic Nephropathy • Hematological Disorders • Inflammation • Metabolic Disorders • Renal Disease • CRP • IL6

Clazakizumab in Chronic Active Antibody-Mediated Kidney Transplant Rejection: Results of the IMAGINE Phase 3 Study (KIDNEY WEEK 2024) - P3 | "Despite encouraging phase 2 results, the data from the IMAGINE IA did not support continuation. Nonetheless, this was the largest placebo-controlled study in KTRs with caAMR and was first transplant study for which the FDA accepted a 1-yr eGFR slope as a RLSE. No safety concerns were noted."

P3 data • Antibody-mediated Rejection • Gastrointestinal Disorder • Immunology • Inflammation • Transplant Rejection • Transplantation • IL6

IL-6 Inhibition with Clazakizumab in Patients Receiving Maintenance Dialysis (KIDNEY WEEK 2024) - No abstract available

Clinical • Nephrology

A to X Nephrology Hot Topics: Autoantibodies, Clazakizumab, Semaglutide (FLOW), and Xenotransplantation (KIDNEY WEEK 2024) - "Learning Pathway(s). Diabetic Kidney Disease Kidney Transplantation ."

Chronic Kidney Disease • Diabetic Nephropathy • Glomerulonephritis • Nephrology • Renal Disease • Transplantation

Combined Dose-Finding and CV Outcomes Study With CSL300 (Clazakizumab) in Adult Subjects With ESKD Undergoing Dialysis (clinicaltrials.gov) - P2/3 | N=2310 | Recruiting | Sponsor: CSL Behring | Enrolling by invitation ➔ Recruiting

Enrollment status • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Dyslipidemia • Nephrology • Renal Disease • CRP

New therapies for highly sensitized patients on the waiting list. (PubMed, Kidney360) - "Administering these agents alone or in combination will advance our ability to effectively desensitize patients and maintain durable suppression post-transplant. After many years of limited options, advanced therapeutics will likely improve efficacy of desensitization and improve access to kidney transplantation for highly-HLA sensitized patients."

Journal • Antibody-mediated Rejection • Transplantation

PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study (clinicaltrials.gov) - P2 | N=395 | Active, not recruiting | Sponsor: University of North Carolina, Chapel Hill | Recruiting ➔ Active, not recruiting | N=600 ➔ 395

Enrollment change • Enrollment closed • Asthma • Immunology • Pulmonary Disease • Respiratory Diseases

Granulomatous Tubulointerstitial Nephritis in a Kidney Allograft: Treatment with Interleukin-6 Receptor Antagonist Stabilises Kidney Function. (PubMed, J Clin Med) - "We revised his underlying diagnosis from cryopyrin-associated periodic syndrome to early-onset sarcoidosis with wild-type NOD2 and established a rationale to use the interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ). We identified 18 reports with 417 unique patients treated with TCZ for indications including HLA-desensitisation, transplant immunosuppression induction, treatment of chronic antibody-mediated rejection, and treatment of subclinical rejection. Both TCZ and the direct IL-6 inhibitor clazakizumab are being studied in ongoing randomised control trials."

Journal • Review • Antibody-mediated Rejection • Immunology • Inflammation • Nephrology • Sarcoidosis • Transplantation

Combined Dose-Finding and CV Outcomes Study With CSL300 (Clazakizumab) in Adult Subjects With ESKD Undergoing Dialysis (clinicaltrials.gov) - P2/3 | N=2310 | Enrolling by invitation | Sponsor: CSL Behring | Active, not recruiting ➔ Enrolling by invitation

Enrollment open • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Dyslipidemia • Nephrology • Renal Disease • CRP

A Phase 2b/3 trial assessing IL-6 inhibition with Clazakizumab in patients with cardiovascular disease or diabetes on dialysis: Results from Phase 2b (ERA-EDTA 2024) - P2/3 | "In patients undergoing dialysis with documented inflammation, clazakizumab resulted in a robust reduction in inflammatory biomarkers that are associated with cardiovascular events and increased albumin. The safety profile of clazakizumab appeared acceptable and consistent with the drug's mechanism of action. These data support continuing to the Phase 3 part of the trial to determine the safety and efficacy of clazakizumab in reducing major cardiovascular events."

Clinical • Late-breaking abstract • P2/3 data • P2b data • Cardiovascular • Diabetes • Hematological Disorders • Infectious Disease • Inflammation • Metabolic Disorders • Neutropenia • Thrombocytopenia • CRP • IL6

IL-6 inhibition with clazakizumab in patients receiving maintenance dialysis: a randomized phase 2b trial. (PubMed, Nat Med) - P2/3 | "The results of this trial indicate that in patients receiving maintenance dialysis, clazakizumab reduced inflammatory biomarkers associated with cardiovascular events. ClinicalTrials.gov registration: NCT05485961 ."

Journal • P2b data • Cardiovascular • Diabetes • Hematological Disorders • Infectious Disease • Inflammation • Metabolic Disorders • Neutropenia • Thrombocytopenia • CRP • IL6

Clazakizumab for Chronic and Active Antibody Mediated Rejection Post-Kidney Transplant (clinicaltrials.gov) - P1/2 | N=10 | Completed | Sponsor: Stanley Jordan, MD | Active, not recruiting ➔ Completed

Trial completion • Antibody-mediated Rejection • Glomerulonephritis • Immunology • Transplant Rejection • Transplantation

A Phase II Trial to Evaluate the Safety and Efficacy of clazakizumab for the desensitisation of highly sensitized patients on the deceased donor kidney transplant waiting list (ANZCTR) - P2 | N=10 | Not yet recruiting | Sponsor: Royal Melbourne Hospital

New P2 trial • Chronic Kidney Disease • Nephrology • Renal Disease • Transplantation

CNI-Free Immunotherapy Combining CTLA-4Ig + Anti-IL-6/IL-6R Results in Long-Term Rejection-Free Graft Survival in Highly-HLA Sensitized Patients (ATC 2024) - "Two patients who showed 100% cPRA & +FCMX at tx were desensitized with clazakizumab (anti-IL6, claza) 25mg/M...Two patients received tocilizumab (anti-IL-6R, toci) and were transitioned to CNI-free regimens at 2 yrs & 11 yrs post-tx... The combination of CTLA4-Ig + anti-IL-6/IL-6R appears to offer benefits in DSA reduction, prevention of dnDSA and allograft rejection after >4 yrs in HS patients. Importantly, CNI toxicity abated in all patients. Recent data from Kubo et al (ATC 2023 shows that IL-6R inhibition with toci attenuates T-cell function and significantly prolongs kidney tx survival in CTLA4-Ig treated monkeys."

Clinical • Transplant Rejection • CD8 • IL6R • NCAM1

Five Year Follow-Up of Highly-HLA Sensitized Patients Desensitized (DES) with Clazakizumab (Anti-IL-6) (ATC 2024) - "All transplanted patients received induction with alemtuzumab and maintained on tac/mmf/pred. Clazakizumab treatment pre- and post-tx exhibited a reasonable safety profile, with no detectable DSA or dnDSA at 2-5yrs post-transplant. This is important since most DES protocols are associated with significant rebound post-tx. Thus, clazakizumab appears promising as a desensitization agent to enable HLAi transplantation especially in patients with CPRA>99.5%."

Clinical • Dermatology • Herpes Zoster • Infectious Disease • Novel Coronavirus Disease • Transplantation • Varicella Zoster • IL6

Anti-IL-6 Therapy Prolongs Nonhuman Primate Cardiac Allograft Survival in a Mixed Chimerism Protocol (ATC 2024) - "*Purpose: We previously achieved tolerance of heart allografts in nonhuman primates (NHPs) by blocking the IL-6 receptor with tocilizumab in a mixed-chimerism protocol where donor bone marrow transplantation (BMT) occurred simultaneously with solid organ transplantation. Here, we investigated the effect of blocking the IL-6 cytokine itself with clazakizumab, to prevent the risk of IL-6 cytokine rebound after the cessation of anti-IL-6 receptor treatment.* Nine cynomolgus NHPs underwent simultaneous BMT and heart transplant with non-myeloablative conditioning including total body and thymic irradiation, ATGAM, anti-CD154 mAb, and cyclosporine until day 28 post-BMT... Adding anti-IL-6 mAb treatment to a simultaneous mixed-chimerism conditioning protocol induced prolonged immunosuppression-free cardiac allograft survival without the rise in CRP observed following anti-IL6R mAb therapy. Future in vitro work will investigate the differences between NHPs with prolonged graft..."

Clinical • Late-breaking abstract • Bone Marrow Transplantation • Cardiovascular • Solid Organ Transplantation • Transplantation • CD40LG • CRP