ABSTRACT
Background: Despite improvements in hemophilia care, challenges remain, including treatment burden and impaired quality of life. Gene therapy may overcome these. However, its introduction presents a challenge. Objectives: To outline a function-based gene therapy working model describing critical milestones associated with gene therapy handling, administration, and follow-up to facilitate and implement an effective infrastructure for gene therapy introduction. Design: Literature review and consensus discussion among Hemophilia Comprehensive Care centers (HCCCs) in the Nordic region. Methods: Representatives from six HCCCs sought to pinpoint milestones and key stakeholders for site readiness at the pre-, peri-, and post-infusion stages, including authority and genetically modified organism (GMO) product requirements, awareness, medical eligibility, logistics and product handling for infusion, laboratory monitoring, and follow-up. Results: A gene therapy transit map was developed with key stakeholders identified. The approach to prepare the vector will differ between the Nordic centers, but the contracted pharmacy unit will be a key stakeholder. Therefore, a pharmacy checklist for the implementation of gene therapy was developed. For the future, Advanced Therapy Medicinal Product centers will also be implemented. Patients' expectations, commitments, and concerns need to be addressed repeatedly and education of patients and the expanded health-care professionals team will be the key to successful and optimal clinical management. Eligibility testing according to the product's summary of product characteristics and frequent follow-up and monitoring post-infusion according to the World Federation of Hemophilia chart will be crucial. Conclusion: The approach to deliver gene therapy in the Nordic region will differ partly between the hemophilia centers, but the defined road map with checklists for the implementation of this advanced therapy will be applicable to all. The map may also serve as a platform for the use of future GMO product options both within and outside the area of hemophilia.
Implementing gene therapy for hemophilia in the Nordic context Why was this study done? ⢠Despite improvements in hemophilia care, challenges remain including treatment burden and impaired quality of life. ⢠Gene therapy may overcome these challenges. ⢠The introduction of gene therapy presents a challenge in many ways. What did the researchers do? ⢠We, as representatives from six Hemophilia Comprehensive Care Centers in the Nordic region, sought to pinpoint milestones and key stakeholders for site readiness at the pre-, peri- and post-infusion stages, including authority and genetically modified organism (GMO) product requirements, awareness, medical eligibility, logistics and product handling for infusion, laboratory monitoring, plus follow-up. What did the researchers find? ⢠We developed a gene therapy transit map and identified key stakeholders. ⢠The approach to prepare the vector will differ between the Nordic centers, but the pharmacy unit will be a key stakeholder. We therefore developed a pharmacy checklist for the implementation of gene therapy. ⢠For the future, Advanced Therapy Medicinal Product centers will be implemented. ⢠Patients' expectations, commitments and concerns need to be addressed repeatedly. ⢠Education of patients and the expanded health care professionals team will be the key to successful and optimal clinical management. ⢠Eligibility testing according to the product's summary of product characteristics and close follow-up and monitoring post-infusion according to the World Federation of Hemophilia chart will be crucial. ⢠Access to both chromogenic and one-stage factor activity assay results from a specialized coagulation laboratory with a short turn-around time is important. What do the findings mean? ⢠The approach to delivering gene therapy in the Nordic region will differ partly between the hemophilia centers, but the defined road map with checklists for the implementation will be applicable to all. ⢠The map may also serve as a platform for the use of future GMO product options both within and outside the area of hemophilia.
ABSTRACT
INTRODUCTION: The use of pharmacokinetic assessment for optimal prophylactic dosing of factor concentrates in haemophilia has gained increasing enthusiasm over the last decade. However, blood sampling on several occasions is burdensome and limited sampling using population-based PK is appealing. AIM: To compare the pharmacokinetics and dosing recommendations for prophylaxis using six-point single subject versus population-based method (WAPPS-Hemo) for simoctocog alfa (Nuwiq® ). METHODS: Twelve adult patients with severe haemophilia A received a factor VIII (FVIII) dose of ≈50 IU/kg, and the activity was measured pre-infusion and at 30 min, 6, 9, 24 and 48 h post-infusion. Half-life (t1 /2 ), weight-normalized AUC and time to troughs of 5%, 3% and 1% were calculated. The correlation between the PK algorithms was assessed using intraclass correlations (ICC) and dosing estimations were provided. RESULTS: WAPPS-Hemo yielded a slightly longer mean t1 /2 , but the overall correlation between the methods was good (ICC ≥0.79) The time to troughs of 5%, 3% and 1% showed ICCs ≥0.86. For all variables, the most converging limited time point was 6+48 h. Additional time points did not improve the correlation. Despite similar pharmacokinetics, the mean estimated dose for a specific trough level varied from 60% less to 20% more using the population-based approach. The time to 1% and the corresponding dose was sensitive to the baseline assumption. CONCLUSION: Our data support the use of population-based PK for patients on simoctocog alfa prophylaxis but also indicates differences, stressing the importance of the sampling scheme and monitoring actual FVIII levels achieved.
