CSL Behring is a biopharmaceutical company, manufacturing plasma-derived and recombinant therapeutic products. Its line of therapies includes products for the treatment of bleeding disorders such as hemophilia and von Willebrand Disease; primary immune deficiencies (PIDD); hereditary angioedema; inherited respiratory disease; and neurological disorders. The company's products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in the newborn.CSL Behring is a combination of Behringwerke, founded in 1904 in Marburg, Germany by Emil von Behring, and the Commonwealth Serum Laboratories (CSL), established in Australia in 1916 to provide vaccines to the people of Australia, as well as other companies acquired since 2004.
Complement and pathogenic antibodies act independently and together to mediate the pathology of many autoimmune diseases. To address these drivers of disease, we generated a monoclonal antibody (mAb), CSL305, that binds and inhibits both complement and the neonatal Fc (fragment crystallizable) receptor FcRn. The fragment antigen binding (Fab) portion of CSL305 was engineered to bind both human C2 (huC2) zymogen and the active fragment huC2b to inhibit the classical and lectin complement pathways in vitro, and C3b deposition on primary lung endothelial cells using a 3-dimensional microvascular model system. Engineering of a triple amino acid mutation (“YPY” motif) into the Fc region of CSL305 increased its affinity to FcRn at both acidic and neutral pH, allowing it to also act as a potent FcRn antagonist. Intracellular trafficking experiments demonstrated that CSL305, but not the wild-type (WT) mAb lacking the YPY motif, was able to block immunoglobulin G (IgG) recycling in vitro. The generation of a high resolution 2.6Å crystal structure of CSL305 Fab region bound to huC2b showed that the epitope lies directly over the huC2b catalytic triad, providing evidence of its complement mechanism of action as a neutralising mAb. Early pharmacokinetic (PK)/pharmacodynamic (PD) studies using CSL305 in cynomolgus monkeys demonstrated both complement inhibition and FcRn antagonism in vivo, with reductions in complement classical pathway activity and endogenous IgG observed following single intravenous (IV) administration. CSL305 thus represents a dual-functional mAb as a potential therapeutic candidate.
HFE -related hemochromatosis (HC) is caused by hepcidin dysregulation and is characterized by excessive iron absorption and accumulation in the liver, heart, and endocrine glands, which leads to complications including arthropathy, cirrhosis, and hepatocellular carcinoma. Standard of care (SoC) typically involves phlebotomy, with iron chelators used less frequently. However, these therapies may cause side effects and negatively impact quality of life, making them troublesome for some patients. Using the Delphi methodology, a survey was developed to identify unmet needs and clinical challenges within the current therapeutic landscape of HC, and to establish consensus statements for its management. Consensus was defined as ≥75% agreement. Thirty-two HC specialists from Europe, Australia and the USA responded to the survey. After three rounds of survey refinement, final consensus statements were compiled. The Delphi process identified key unmet needs in HC, including lack of alternatives to phlebotomy, persistent symptoms, and burden related to the use of current SoC. The consensus process helped establish definitions for high phlebotomy treatment burden, intolerance, and suboptimal response to phlebotomy. The process also identified the subgroup of patients overly burdened by phlebotomy. Patient-reported outcomes were considered key to assessing phlebotomy’s impact, although they are rarely measured in clinical practice. The Delphi study highlighted the limitations of phlebotomy, with respondents identifying a high unmet need for patients who cannot be managed with or do not tolerate this approach. The study suggested exploring alternative therapy options for patients who experience high treatment burden or intolerance to phlebotomy.
Background Factor XIII (FXIII) deficiency increases bleeding risk and delays wound healing, yet its recognition, diagnosis, and treatment remain challenging in the complex clinical routine. Objective To determine real-world diagnosis and management strategies of acquired FXIII deficiency. Methods Adult patients undergoing FXIII activity testing (diagnostic phase) and FXIII supplementation (treatment phase) for acquired FXIII deficiency were consecutively enrolled in this retrospective data collection. Treatment outcomes were analyzed in patients with postsurgical bleeding and wound healing disorders (WHD). Results A total of 255 patients were included in the diagnostic cohort, of whom 84% were diagnosed with clinically relevant FXIII deficiency and 77% received FXIII supplementation. Median FXIII activity in patients with a clinically relevant deficiency was 42.5%, compared to 74.0% in those without. Most patients with FXIII activity levels below 60% were considered to have a clinically relevant deficiency. The treatment cohort comprised 96 postsurgical bleeding cases and 78 WHD cases. Median FXIII activity levels were similarly reduced in both cohorts (44.0% vs 48.0%). Conventional coagulation tests remained mainly within reference ranges for most patients, highlighting the diagnostic gap. Persistent infection was the leading comorbidity, affecting 33% of patients in both cohorts. Conclusion In this real-world setting, FXIII supplementation was most frequently initiated at FXIII activity levels below 60%-70%. These findings suggest using this range as a clinical reference point for therapeutic intervention, while bearing in mind the exploratory nature of the data. Routine FXIII testing should be considered in patients with unexplained bleeding or impaired wound healing, particularly perioperatively, after major trauma, or with persistent infections.
