Jerzy Windyga

Denecimig (Mim8) is a next-generation, activated factor VIII mimetic, fully human bispecific immunoglobulin G4 antibody in development for subcutaneous prophylaxis in bleeding episodes, for patients with hemophilia A (HA) with/without inhibitors. FRONTIER4 is an open-label extension study to assess the safety and efficacy of denecimig. Here we present an interim analysis of patients receiving denecimig once every 2 weeks (Q2W) in FRONTIER4. Patients with HA aged ≥12 years who had participated in the denecimig phase 2 study and ≥12 weeks of its extension and entered arm 1 of the FRONTIER4 phase 3 study received denecimig Q2W for 26 weeks using a tiered dosing approach according to body weight range. The primary end point was the number of treatment-emergent adverse events (TEAEs); secondary end points included injection site reactions, occurrence of anti-denecimig antibodies, denecimig plasma concentrations, and number of treated bleeds. Thirty-seven patients were enrolled who received denecimig for a mean of 1.73 years in the phase 2 study. Sixty TEAEs were reported in 20 patients. Most TEAEs were mild/moderate in severity (98.3%), unlikely to be related to denecimig (75.0%), and resolved during the time frame of this analysis (90.0%). No TEAEs led to permanent discontinuation of denecimig, and none were fatal. Two patients reported 14 injection site reactions. Denecimig plasma concentrations were stable through week 26. The estimated mean annualized bleeding rate was 0.38 bleeds per patient year. Most patients experienced zero treated bleeds (83.8%). In summary, denecimig administered Q2W was well tolerated, with few patients experiencing treated bleeds and no safety concerns. This trial was registered at www.clinicaltrials.gov as NCT05685238.

Background: Paroxysmal nocturnal haemoglobinuria (PNH) is characterised by complement-mediated haemolysis. Pegcetacoplan (PEG), a proximal complement inhibitor, offers alternative treatment for patients with suboptimal responses to C5 inhibitors (C5i). Objective: To evaluate the real-world effectiveness and safety of PEG in PNH patients from Central and Eastern Europe (CEE) not responding optimally to C5i therapy. Design: A multicentre, retrospective, observational cohort study. Methods: This retrospective study analysed 26 adult patients who were switched to PEG therapy due to persistent anaemia despite C5i therapy. The patient inclusion period covered January 2023 to January 2025; data collection was conducted in February 2025, and the median treatment duration with PEG was 11.8 months. Key outcomes included haemoglobin levels, transfusion independence, and management of breakthrough haemolysis (BTH). Results: PEG therapy resulted in a mean haemoglobin increase of 3.24 g/dL, normalisation of reticulocytosis and bilirubinaemia, and transfusion independence in 76.9% of patients. BTH events were effectively managed with dose adjustments or additional C5i, with no treatment discontinuations. Conclusion: PEG demonstrates high efficacy in improving haemolysis control and clinical outcomes in PNH patients presenting with anaemia despite C5i therapy, aligning with PEGASUS trial findings and highlighting effective BTH management strategies.

Recombinant ADAMTS13 (rADAMTS13) was approved for prophylactic or on-demand ADAMTS13 replacement therapy for congenital thrombotic thrombocytopenic purpura (TTP) based on data from a preplanned interim analysis of a phase 3, open-label, crossover trial (NCT03393975). Here, we report results from the final analysis with 48 participants (3-68 years old) randomized 1:1 to two 6-month periods of prophylaxis with rADAMTS13 (40 IU/kg) or plasma-based therapy (PBT), followed by the alternate treatment at the same frequency; thereafter, all participants received 6 months of rADAMTS13. The primary outcome was acute TTP events. No participants experienced an acute event during rADAMTS13 prophylaxis, whereas 1 experienced an acute event during PBT prophylaxis (mean annualized event rate [AER], 0.04). A lower model-based mean AER of subacute TTP events was observed during rADAMTS13 prophylaxis (0.04) versus PBT (0.26). Thrombocytopenia was the most frequent TTP manifestation (model-based mean AER, 0.91 with rADAMTS13 and 1.62 with PBT). Treatment-related adverse events (AEs) occurred in 4.3% of participants with rADAMTS13 and in 45.8% with PBT. No serious AEs were considered related to rADAMTS13, whereas 1 serious AE (pyrexia) was considered related to PBT. No ADAMTS13-neutralizing antibodies were detected. Greater treatment satisfaction was reported for rADAMTS13 prophylaxis versus PBT (assessed using the 9-item Treatment Satisfaction Questionnaire for Medication). A ~6-fold increase in ADAMTS13 activity and prolonged time with ADAMTS13 activity of ≥10% was noted in participants receiving rADAMTS13 versus PBT. Consistent with the interim analysis, results with a longer follow-up support the continued clinical benefit of rADAMTS13 prophylaxis in congenital TTP.

This article presents recommendations aimed at reducing the risk of bleeding during bronchoscopy. The document was developed by a working group convened by the Polish Respiratory Society, which included pulmonologists experienced in bronchoscopic procedures, an anesthesiologist, a thoracic surgeon, a cardiologist, a hematologist, a nurse, and methodologists. Clinical questions were formulated according to the PICO (Population, Intervention, Comparison, Outcome) framework, followed by a systematic literature search and critical appraisal of the selected studies. Based on these data, 13 recommendations/good clinical practice points were developed addressing bronchoscopy in patients with thrombocytopenia, abnormal activated partial thromboplastin time or international normalized ratio results, and in those receiving antiplatelet agents, oral anticoagulants, or low-molecular-weight heparin.

Concizumab is a novel non-factor-replacement therapy intended for once-daily subcutaneous prophylactic treatment of hemophilia A/B with and without inhibitors. Superiority was confirmed for concizumab compared with on-demand treatment in patients with hemophilia A/B without inhibitors (HA/HB) in the prospective, multicenter, open-label phase 3 explorer8 study. Here, longer‑term efficacy and safety results from the start of the study up to the 56-week cut-off are presented. Males aged ≥12 years with HA/HB were randomized 1:2 to no prophylaxis (group 1) or concizumab (group 2), or allocated to concizumab (groups 3/4). Assessments at the 56-week cut-off included measures of efficacy, pharmacokinetics/pharmacodynamics, and safety. The 56-week cut-off was defined as when all patients in group 2-4 had completed the visit at 56 weeks or permanently discontinued treatment. Of 148 patients in the full analysis set, 21 were randomized to no prophylaxis (group 1: HA, n=9; HB, n=12), 42 to concizumab (group 2: HA, n=18; HB, n=24) and 85 were assigned to the non-randomized concizumab groups 3/4 (HA, n=55; HB, n=30). After ≥24 weeks of treatment, 17 patients in group 1 switched to concizumab. Low median annualized bleeding rates for treated spontaneous and traumatic bleeding episodes were maintained at the 56-week cut-off in patients receiving concizumab (HA: 1.7 [interquartile range, 0.0; 4.5]; HB: 2.8 [0.0; 6.4]), consistent with 32‑week cut‑off results. Concizumab plasma concentration remained stable over time and no new safety concerns were reported. Concizumab showed longer-term efficacy in patients with HA/HB at the 56-week cut-off and was considered safe and well tolerated. ClinicalTrials.gov; NCT04082429.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled complement activation that leads to hemolysis and thrombosis. Clinical outcomes have dramatically improved with administering terminal and proximal complement inhibitors (CIs). However, these treatments come at the cost of increasing the risk of severe infection, especially from encapsulated bacteria. This has created compulsory vaccination recommendations by regulatory authorities to patients with PNH on CIs treatment. Material and methods: An adaptation of the Delphi consensus process involving a group of experts in the field of hematology, infectious diseases, and vaccinology was used to develop Polish vaccination recommendations for patients with PNH treated with CIs. The experts reviewed 16 proposed statements, rating each from 1 to 9 in 3 rounds (1–3 denoted as “disagree,” 4–6 as “neutral” and 7–9 as “agree”). A final decision on statements that were converged to strong or even moderate agreement was taken into practice. Results: A Delphi process ended with convergence into consensus all 16 prepared statements. Recommendations include routine immunization against meningococcus (MenACWY, MenB) in patients on proximal and terminal CIs, extended immunization against Streptococcus pneumoniae and Haemophilus influenzae type b in patients on proximal CIs, and the use of antibiotic prophylaxis against meningococcal infection in patients where the institution of CI therapy cannot be delayed until vaccines have been given. Annual immunizations against influenza and COVID-19 are also recommended. Conclusions: These consensus guidelines emphasize the paramount importance of optimal immunization for PNH patients treated with CIs. Completing vaccination schedules and implementing prophylactic strategies may significantly reduce the risk of severe, potentially life-threatening infections, thus allowing for safer and more effective management of the disease. Keywords: Meningococcal Vaccine Pneumococcal Vaccine Haemophilus influenzae b Vaccine Complement-mediated hemolysis Infection prevention in PNH

Introduction: Acquired hemophilia A (AHA) is a rare and serious bleeding disorder that poses significant treatment challenges due to its sudden onset and the risk of severe bleeding episodes. Material and methods: This study is a retrospective analysis of data from 10 adult patients with AHA who were treated with recombinant porcine factor VIII (rpFVIII). Specifically, the benefits and challenges of using susoctocog alfa for the treatment of AHA were examined. Results: This case series highlights the efficacy of rpFVIII, particularly in providing essential coagulation support during surgery or invasive procedures, thereby reducing the risk of hemorrhagic complications. Despite the presence of comorbidities that increase the risk of thrombosis, none of the patients experienced thrombotic complications during rpFVIII treatment, indicating a satisfactory safety profile of the drug. Discussion: The analysis showed that rpFVIII is a versatile and effective hemostatic treatment option for patients with AHA, with a clear advantage over bypassing agents in invasive procedures. The laboratory monitoring available with rp-FVIII allows for a more accurate dosing to meet the individual needs of patients, potentially reducing the risk of thrombosis. This is particularly important in elderly patients with AHA, who may be more susceptible to thrombotic events. Conclusions: Overall, the article confirms that rpFVIII is a valuable and effective option in the comprehensive management of AHA.

Introduction: The population pharmacokinetic (PK) analysis of clotting factor VIII (FVIII) enables individual PK value estimation and hemophilia treatment personalization. Aim: To compare the number of bleeding episodes and standard half-life (SHL) FVIII (SHL-FVIII) consumption before and after PK-based dosing adjustment in adult patients with severe hemophilia A. Material and methods: The prospective, 18-month study had 3 phases: (1) before FVIII dosing adjustment, (2) dosing adjustment based on FVIII PK analysis, (3) after FVIII dosing adjustment. During phase 1 and 3 of the study, patients frequently changed SHL-FVIII concentrates and recorded FVIII consumption and bleeds in electronic diaries (myPKFiT® licensed for octocog alfa). In phase 2, PK analysis was performed following the infusion of octocog alfa. Annualized bleeding rates (ABRs) and SHL-FVIII consumption in phases 1 and 3 were compared. Results: The clearance of octocog alfa ranged from 0.014 to 0.051 dL/h/kg, half-life-from 9.1 to 27.9 h, and time to reach 1 IU/dL-from 51 to 179 h. Seventeen from 22 included male patients modified treatment according to the PK analysis, which resulted in decreases of 3.1-fold in total ABR (p = 0.02), 3.3-fold in spontaneous ABR (p = 0.0), and 3.1-fold in injury-related ABR (p = 0.072) compared to phase 1. The total consumption of SHL-FVIII increased by 16.8% (p = 0.052), and the consumption due to bleeds decreased by 77% (p = 0.034) Conclusions: Personalizing FVIII replacement therapy lowers bleeding risk with not statistically significant increased drug consumption in patients with severe hemophilia A. Treatment based on octocog alfa PK analysis was successfully applied to other SHL-FVIII products.

Introduction: Eptacog beta is an activated recombinant human factor VII bypassing agent approved for treating bleeding episodes (BEs) in patients aged ≥12 years with haemophilia A or B with inhibitors. Two initial dose regimens (IDRs) of either 75 or 225 µg/kg, followed by 75 µg/kg, are approved. We examined the safety of eptacog beta 225 µg/kg across completed clinical trials. Methods: This analysis included data from a Phase 1b trial of single doses of eptacog beta 25, 75 and 225 µg/kg in non‐bleeding adults with haemophilia and pooled data from two Phase 3 trials of the 75 and 225 µg/kg IDRs for treating BEs in adolescents and adults (PERSEPT 1) and children (PERSEPT 2). Results: In the Phase 1b trial, 10 patients received a single eptacog beta infusion at each dose level. In the Phase 3 trials, 48 patients received the 75 µg/kg IDR (median 20.5 infusions/patient, range 1–137 infusions) and 50 patients received the 225 µg/kg IDR (median 14.5 infusions/patient, range 1–117 infusions). There was a similar incidence of treatment‐emergent adverse events (TEAEs) across all doses (225, 75 and 25 µg/kg) in the Phase 1b trial (0.8 vs. 1.0 vs. 2.1 events per infusion, respectively) and with the 225 versus 75 µg/kg IDR in the Phase 3 studies (0.046 vs. 0.029 events per infusion, respectively). No treatment‐related serious TEAEs, thromboembolic events, hypersensitivity reactions, deaths attributed to eptacog beta or neutralising antibodies were detected. Conclusions: These findings demonstrate favourable safety and tolerability regarding the use of the 225 µg/kg IDR. Trial Registration: ClinicalTrials.gov identifier: NCT01708564, NCT02020369, NCT02448680

DOI: 10.20452/pamw.16993, Published online: April 08, 2025, Authors: Jerzy Windyga¹, Riitta Lassila²