Plasma proteomics and collagen biomarkers in people with haemophilia A receiving emicizumab in STASEY

Introduction Recurrent joint bleeds in people with haemophilia A (PwHA) can cause joint damage, which releases proteins involved in processes such as cartilage remodelling (e.g. collagen), inflammation and angiogenesis (e.g. cytokines, growth factors) into the blood. Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F)IX and FX, mimicking the cofactor function of activated FVIII and restoring haemostasis in PwHA. The aim was to measure biomarkers of tissue and joint destruction to understand the effects of emicizumab prophylaxis on joint health. Method Following informed consent and ethics committee approval, PwHA with FVIII inhibitors aged≥12 years in the Phase 3b Roche-sponsored STASEY study (NCT03191799) received once-weekly 1.5mg/kg maintenance dosing of emicizumab. Serum and plasma samples from 113 PwHA were collected after overnight fasting at baseline, and following 6 months and 2 years of emicizumab. Separately, samples were collected from 20 healthy volunteers (HV). Collagen degradation and formation products were measured using immunoassays against C4M, PRO-C4, PRO-C8, C2M, PRO-C2, and PRO-C18 (Nordic Bioscience). Proteomic analysis of 2926 proteins was performed (Olink). Differences in expression were identified using linear regression and linear mixed model regression, with p-values adjusted for multiple testing (Benjamini-Hochberg). Results PRO-C8 (collagen 8 synthesis) was higher in PwHA vs. HV and decreased with emicizumab treatment; PRO-C2 and C2M (collagen 2 markers of cartilage formation and degradation) increased with treatment, indicating cartilage remodelling ([ Fig. 1 ]). Proteomics analysis showed upregulation of inflammatory response, angiogenesis, coagulation and complement pathways in PwHA vs. HV at baseline, and downregulation upon emicizumab treatment. Proteomics also showed upregulation of selected pathways related to osteoporosis, arthropathy, and arthritis in PwHA vs. HV and downregulation upon emicizumab treatment ([ Fig. 2 ]). Fig. 1 Expression of selected collagen degradation and formation products in HV and PwHA at baseline (A–C) and in PwHA after 6 months and 2 years of emicizumab treatment (D–F). The plots represent median expression and 25% and 75% quartiles. Linear regression and linear mixed model regression were used to identify differences in expression. P-values were adjusted for multiple testing using the Benjamini-Hochberg method and results with adjusted p-values