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56. Jahrestagung der Deutschen Gesellschaft für Transfusionsmedizin und Immunhämatologie

Prof. Dr.

Vorsitz

PD Dr.

Neue Therapieansätze in der Hämophilie

eingeladene Redner

Vortrag

Mausmodelle in der Thrombose- und Hämostaseforschung

Prof.

Quantitative pharmacokinetic model to characterize and extrapolate long-term FVIII activity levels in patients with severe hemophilia A treated with valoctocogene roxaparvovec

Hemostaseology

Background Valoctocogene roxaparvovec delivers a B-domain deleted factor VIII (FVIII) coding sequence with an adeno-associated virus vector to reduce bleeding and FVIII concentrate use in people with severe hemophilia A. The aim is to characterize the long-term trajectory of transgene-derived FVIII activity using a linear mixed effects (LME) model to estimate mean and median FVIII activity levels 5 years post-infusion.Methods In GENEr8-1, an open-label, single-arm, multicenter phase 3 trial, 134 participants with severe hemophilia A received a single 6x1013 vg/kg dose of valoctocogene roxaparvovec. FVIII activity was assessed using the chromogenic substrate assay and one-stage assay.i Ln-transformed FVIII activity values from week 76 to 104 were fit to the LME model with random effects for participants on slope and intercept using a restricted maximum likelihood method with the lmer package in the R software. The precision of parameter estimates and model diagnostics were evaluated to confirm goodness-of-fit. The model and extrapolation approach was further qualified by comparing to observed FVIII activity at week 156.Results A previously published quantitative pharmacokinetic (PK) modelii was updated to extrapolate FVIII activity levels to 5 years post-infusion. The final LME model dataset included 928 observations from 120 participants. The long-term trajectory of FVIII activity was consistent with first-order elimination kinetics starting at week 76. Model parameter estimates were consistent with the previously published model as shown in Table 1; diagnostic plots showed no major deficiencies. FVIII activity was extrapolated to 5 years post-gene transfer (Table 2). Mean and median FVIII activity extrapolations at week 156 were consistent with observed values, confirming adequacy of the model.Conclusion Pharmacokinetic modeling indicates valoctocogene roxaparvovec-derived FVIII activity levels will remain in the mild hemophilia range for ≥5 years post-gene transfer for the majority of patients treated. Offenlegung Interessenkonflikt: Marco Stadler is an employee of BioMarin Pharmaceutical. References i Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med 2022;386:1013-25. ii Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. N Engl J Med. 2023;388(8):694-705. doi:10.1056/NEJMoa2211075

Freier Vortrag

Prevalence of anti-PF4/Heparin antibodies after second COVID-19 vaccination in healthcare workers

Background Anti-platelet factor 4 (PF4) antibodies have been identified as the cause of vaccine-induced immune thrombotic thrombocytopenia following adenoviral vector-based COVID-19 vaccines. Previous studies have primarily focused on determining the frequency of anti-PF4 antibodies shortly after the first COVID-19 vaccination, leaving the rates of anti-PF4 antibody positivity after second vaccinations largely unknown.Methods In this study, we analyzed serum samples from healthcare workers who had received at least two vaccines, with the first vaccine being the AstraZeneca (AZ) vaccine. Anti-PF4/heparin IgG antibody levels were determined using a commercially available ELISA kit. An optical density (OD) greater than 0.5 was considered a positive result.Results A total of 444 study participants (356 (80%) females and 88 (20%) males) with a median age of 48 years (ranging from 21 to 67 years) were included in this study. Serum samples were collected a median of 158 days (range: 76 to 209 days) after the second vaccination. Of the samples analyzed, 27 (6%) were positive by ELISA with a median OD of 0.728 ranging from 0.5 to 2.8. Specifically, there were 5 of 93 cases (5.3%) in individuals who received two AZ vaccinations, 15 of 226 cases (6.6%) in individuals who received AZ-Biontech/Pfizer vaccinations, and 7 of 125 cases (5.6%) in individuals who received AZ-Moderna vaccinations. Investigations into the platelet activation properties of these antibodies are ongoing.Conclusion The observed frequency of positive cases is consistent with findings from previous studies conducted after the first vaccination. However, the presence of cases with high OD values and the time elapsed since the second vaccination suggest the need for further studies to fully evaluate the clinical significance of vaccine-induced anti-PF4 antibodies.Offenlegung Interessenkonflikt: keine

MOA 15

Sektion Hämostaseologie

Sektionssitzungen

Sektion Hämostaseologie

Appointment

Vorsitz

Programme