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

CLARITY-CRP: A Study of Clazakizumab (LY5724886) in Adults With Elevated hsCRP and at Increased Risk for Cardiovascular Event (clinicaltrials.gov) - P2 | N=120 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Diabetes • Genetic Disorders • Hypertension • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus • CRP

Targeting Inflammation in Chronic Kidney Disease: Pathophysiological Insights and Emerging Therapeutic Strategies. (PubMed, J Clin Med) - "Renin-angiotensin system inhibitors, sodium-glucose cotransporter-2 inhibitors, finerenone, and glucagon-like peptide-1 receptor agonists improve cardiorenal outcomes and have plausible anti-inflammatory actions, although inflammatory mediation remains unproven...Interleukin-6 ligand inhibition produces marked human target engagement; however, headline results from the completed phase 3 ZEUS trial showed no reduction in three-point major adverse cardiovascular events with ziltivekimab despite biomarker suppression, while serious infections were more frequent. POSIBIL6ESKD continues to test clazakizumab in inflamed dialysis patients...Future progress requires inflammatory endotyping, repeated biomarker assessment, mechanistically aligned outcomes, and rigorous infection surveillance. ZEUS underscores that pathway suppression must deliver clinical benefit beyond contemporary standard therapy."

Journal • Review • Cardiovascular • Chronic Kidney Disease • Fibrosis • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Nephrology • Renal Disease • IL6 • NLRP3

Treatment of antibody-mediated rejection in heart transplantation: from empirical combination to multi-target precision intervention. (PubMed, Front Immunol) - "Over the past decade, agents targeting plasma cells (proteasome inhibitor bortezomib), the terminal complement component (C5 monoclonal antibody eculizumab), the IL-6 pathway (tocilizumab, clazakizumab), and the more recent anti-CD38 monoclonal antibody (daratumumab) have entered clinical practice, shifting AMR treatment from having no actionable targets to enabling multi-node intervention. Consensus is lacking on how to select, combine, and sequence these agents based on individual immune phenotypes. Stratified therapy, dynamic biomarker monitoring, and rational multi-target combination will be the core directions for solving this challenge in the coming decade."

IO biomarker • Journal • Review • Antibody-mediated Rejection • Cardiovascular • Immunology • Transplantation • IL6

CLARITY-CRP: A Study of Clazakizumab (LY5724886) in Adults With Elevated hsCRP and at Increased Risk for Cardiovascular Event (clinicaltrials.gov) - P2 | N=120 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P2 trial • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Diabetes • Genetic Disorders • Hypertension • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Type 2 Diabetes Mellitus • CRP

A Phase 1b Study to Evaluate the PK of CSL300 (Clazakizumab) in Chinese Subjects With End Stage Kidney Disease (ESKD) (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: CSL Behring

New P1 trial • Chronic Kidney Disease • Nephrology • Renal Disease

Reply to Comment on "Clazakizumab in the treatment of chronic active antibody-mediated kidney transplant rejection: Results from the IMAGINE phase 3, randomized, double-blind, placebo-controlled study". (PubMed, Am J Transplant) - No abstract available

Clinical • Journal • P3 data • Antibody-mediated Rejection • Immunology • Transplant Rejection • Transplantation

Daratumumab Reduces Microvascular Inflammation and Stabilizes Graft Function in Chronic Active Antibody-Mediated Rejection: A Target Trial Emulation (ATC 2026) - "After early termination of the IMAGINE trial investigating clazakizumab for AMR due to futility, daratumumab became available under compassionate use at our center.* We emulated a target trial comparing daratumumab with placebo in kidney transplant recipients with biopsy-proven chronic active AMR. In this placebo-controlled target trial emulation, daratumumab reduced microvascular inflammation and stabilized graft function in chronic active AMR, supporting CD38-targeted therapy as a promising treatment strategy."

IO biomarker • Antibody-mediated Rejection • Hematological Malignancies • Inflammation • Multiple Myeloma

Felzartamab, an Anti-CD38 Antibody, in Late AMR: Efficacy Independent of Prior Rejection History or Therapy (ATC 2026) - P1, P2 | "In total, 11 patients underwent immunoadsorption-based desensitization (n=8) and/or anti-humoral therapy (n=6), the latter including plasmapheresis (n=2), rituximab (n=2), IVIG (n=1), tocilizumab (n=1), clazakizumab (n=2), and/or the C1s monoclonal antibody BIVV009. Five patients had previously participated in AMR trials evaluating clazakizumab (NCT03444103; n=2), imlifidase (NCT03897205; n=1; control), bortezomib (NCT01873157; n=2; placebo), or BIVV009 (NCT02502903; n=1). Felzartamab is able to reverse AMR, even in patients with a long-standing rejection history and different forms of previous rejection treatment."

Clinical • Antibody-mediated Rejection • Inflammation

Advancing beyond stand-alone NAb assays: perspectives and regulatory impact of applying integrated immunogenicity assessment in drug development. (PubMed, Bioanalysis) - "Two case studies involving low-risk monoclonal antibodies-garadacimab and clazakizumab-are presented, in which validated standalone NAb assays were available but not relied upon for primary clinical interpretation due to limited sensitivity and lack of added clinical value. In both cases, this approach enabled clear differentiation between detectable but clinically irrelevant immunogenicity and immunogenicity with clinical consequence and was accepted by regulatory authorities. These examples illustrate how integrated immunogenicity assessments can replace standalone NAb assays while remaining scientifically rigorous, clinically informative, and aligned with regulatory expectations."

Journal

Improving Physical Function in Older Adults Using an Anti-inflammation Drug: The RIGHT Study (clinicaltrials.gov) - P2 | N=29 | Completed | Sponsor: Anne B. Newman | Active, not recruiting ➔ Completed

Trial completion • Inflammation • IL6

Comment on "Clazakizumab in the treatment of chronic active antibody-mediated kidney transplant rejection: Results from the IMAGINE phase 3, randomized, double-blind, placebo-controlled study". (PubMed, Am J Transplant) - No abstract available

Clinical • Journal • P3 data • Antibody-mediated Rejection • Immunology • Transplant Rejection • Transplantation

The anti-interleukin-6 antibody ALD518-P18 mitigates murine kidney ischemia-reperfusion injury. (PubMed, Sci Rep) - "The antibody attenuated inflammation, endothelial activation and pSTAT3 signalling, significantly downregulating gene expression of the acute tubular stress marker NGAL. These findings confirm the pathogenic role of IL-6 and highlight its early blockade with cALD518-P18 as a promising therapeutic strategy to improve outcomes in acute kidney injury and transplantation."

Journal • Preclinical • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • Transplantation • IL6 • IL6R

Combined Dose-Finding and CV Outcomes Study With CSL300 (Clazakizumab) in Adult Subjects With ESKD Undergoing Dialysis (POSIBIL6ESKD) (clinicaltrials.gov) - P2/3 | N=3110 | Recruiting | Sponsor: CSL Behring | N=2310 ➔ 3110

Enrollment change • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease

CTLA4-Ig + Anti-IL-6/IL-6R Treatment Results in Long-term Allograft Survival and Function in Highly HLA-sensitized Patients. (PubMed, Transplant Direct) - "Clazakizumab and tocilizumab treated patients showed improvements in RF, with elimination of existing DSAs, except for 1 patient and no dn-DSAs (>6 y). Combining CTLA4-Ig + anti-IL-6/IL-6R appears to offer benefits in sustaining RF, DSA reduction, possibly immune cell modulation, and prevention of dn-DSA. Importantly, CNI toxicity abated in all patients."

Journal • Antibody-mediated Rejection • Immune Modulation • Immunology • Transplantation • CD8 • IL6R

Clazakizumab for Chronic Active Antibody Mediated Rejection: Lessons from the IMAGINE trial and the Path Forward. (PubMed, Am J Transplant) - No abstract available

Journal • Antibody-mediated Rejection • 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 | Trial completion date: Sep 2029 ➔ May 2029 | Trial primary completion date: Sep 2029 ➔ May 2029

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

Clazakizumab in the treatment of chronic active antibody-mediated kidney transplant rejection: Results from the IMAGINE phase 3, randomized, double-blind, placebo-controlled study. (PubMed, Am J Transplant) - "No safety concerns were noted. In conclusion, IL-6 blockade with clazakizumab did not translate into improvement in eGFR in KTx recipients with caAMR."

Clinical • Journal • P3 data • Antibody-mediated Rejection • Immunology • Transplant Rejection • Transplantation

PrecISE (Precision Interventions for Severe and/or Exacerbation-Prone Asthma) Network Study (clinicaltrials.gov) - P2 | N=950 | Completed | Sponsor: University of North Carolina, Chapel Hill | N=395 ➔ 950

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

Effect of Clazakizumab on Neutrophil-Lymphocyte Ratio in Patients Receiving Hemodialysis: Secondary Analysis of the POSIBIL6ESKD Phase 2b Trial. (PubMed, Clin J Am Soc Nephrol) - No abstract available

Journal • P2b data • Cardiovascular • Diabetes • Inflammation • Metabolic Disorders

Eli Lilly Enters $100 Million Licensing Agreement with CSL Limited for Clazakizumab (PharmExec)

Licensing / partnership • Cardiovascular • Transplant Rejection

The "Reducing Inflammation for Greater Health Trial (RIGHT)" Study-Concept, Rationale, and Design. (PubMed, J Am Geriatr Soc) - P2 | "Clazakizumab, a monoclonal antibody targeting IL-6, 5 mg via subcutaneous injection every 4 weeks for 24 weeks compared to a placebo...The study was approved by the IRB and is registered with ClinicalTrials.gov (NCT05727384). The RIGHT study will inform the geroscience hypothesis that modifying aging itself will lead to improvement in multiple aspects of health."

Clinical • Journal • Infectious Disease • Inflammation • Oncology • CRP • IL6

Improving Physical Function in Older Adults Using an Anti-inflammation Drug: The RIGHT Study (clinicaltrials.gov) - P2 | N=29 | Active, not recruiting | Sponsor: Anne B. Newman | N=60 ➔ 29

Enrollment change • Alzheimer's Disease • Inflammation • IL6

Clazakizumab: A Therapeutic Approach for Patients With Late Antibody-Mediated Rejection. (PubMed, Kidney Int Rep) - No abstract available

Journal • Antibody-mediated Rejection

The Effects of Clazakizumab on Peripheral Blood and Kidney Transcriptomes in Patients With Late Antibody-Mediated Rejection. (PubMed, Kidney Int Rep) - "We also found a kidney plasma cell gene-rich module that positively correlated with circulating DSAs; however, this was not significantly downregulated by CLZ. Overall, our results provide mechanistic insights into the effects and limitations, of IL-6 neutralization in humans in the context of AMR."

Journal • Antibody-mediated Rejection • Inflammation • IL6

Effect of Clazakizumab on Neutrophil-to-Lymphocyte Ratio in Patients Receiving Maintenance Hemodialysis: Secondary Analysis of the POSIBIL6ESKD Phase 2b Trial (KIDNEY WEEK 2025) - "The Phase 3 component of the trial will provide definitive evidence on the effects of clazakizumab on CV outcomes in this population. Figure: Repeated measures of NLR for the placebo and pooled clazakizumab groups"

Clinical • P2b data • Atherosclerosis • Cardiovascular • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • CRP • IL6