Model-based dose selection for gene therapy for haemophilia B

Abstract Haemophilia B, also known as the Christmas disease, named after Stephen Christmas the first patient diagnosed with this disease, is an inherited disease caused by a defect in the Factor IX Gene ( F9 ). This defect manifests in insufficient production of the blood coagulation factor IX, resulting in excessive bleeding. The therapy which is mainly used involves prophylactic infusions of factor IX concentrate to improve the quality of life by minimising the episodes of bleeds. The main limitations of such a treatment plan are repeat infusions, product half-life, costs and inhibitor formation. The FIX concentration in healthy individuals is typically 90 nM and based upon the experience of the clinicians increasing FIX activity to 1–5 % of normal values has significant impact on patients’ quality of life. Therefore, even a partial correction the FIX deficiency would result in improved clinical outcomes and increase the chances of patients living a near-normal life. Gene therapy has the potential to deliver this, and the fact that haemophilia B is monogenic in nature further encourages the exploration of gene delivery for this disease. In this chapter, an integrated Pharmacokinetic (PK) – Pharmacodynamic (PD) model that has been developed using the clinical data is reported. The key features of the model are that it considers the pharmacological response, i.e., plasma FIX coagulation activity level as well as the toxicological response, i.e., the level of serum alanine aminotransferase. The simulation-based PK-PD modelling approach is then used for the initial dose selection to provide clinicians with better tools to simplify the decision-making process for designing more effective treatment plans, which can be tailored to maximise efficacy while minimising toxicity for individual patients.