Abstract Number: PB0526
Meeting: ISTH 2021 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical
Background: Fitusiran is an investigational, subcutaneously administered, small interference RNA therapeutic that targets antithrombin (AT) and restores thrombin generation sufficient to rebalance hemostasis in people with hemophilia A/B, with/without inhibitors.
Aims: This analysis aimed to characterize the AT dynamics by PopPK/PD model and predict dosing regimens to mitigate the risk of vascular thrombotic events.
Methods: AT activity data from phase 1 (NCT02035605) and phase 2 (NCT02554773) studies in healthy subjects and people with hemophilia A or B, with or without inhibitors were used to develop the PopPK/PD model. The model was externally validated using AT activity data from phase 3 studies (NCT0341710, NCT03417245 and NCT03549871). The PopPK/PD model was further used to simulate AT activity at various dosing regimens in 1000 virtual patients.
Results: The PopPK/PD dataset included 1752 AT activity observations from 45 subjects. A modified indirect response (Figure 1) PopPK/PD model described the dynamics and variability in AT activity reasonably well. Simulations showed that with starting dose of 50 mg Q2M, >90% patients (10th percentile trough-AT activity = 15.3%) would achieve AT activity >15%; the median peak AT activity is projected to be 32.4%, indicating that ~50% patients may have AT activity >35%. For these patients, a dose escalation to 50 mg QM would be required to achieve AT activity <35%. Amongst patients switching to 50 mg QM regimen, if any patients still have peak AT activity >35%, another escalation to 80 mg QM is recommended.
Conclusions: The AT activity profile and inter-patient variability were well characterized by PopPK/PD model. Simulations using this model supported the thrombosis risk mitigation scheme to start with a subcutaneous dose of fitusiran at 50 mg Q2M, if needed escalate to 50 mg QM, and in limited cases, to further escalate to 80 mg QM, based on AT levels.
Schematic of the PopPK/PD model
To cite this abstract in AMA style:
Bhagunde P, Ge S, Iqbal S, Mei B, Andersson S, Kanamaluru V, Lu Q. Fitusiran Population Pharmacokinetic and Pharmacodynamic (PopPK/PD) Modeling to Support Revised Dose, Dosing Regimens & Dose Mitigation Scheme [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/fitusiran-population-pharmacokinetic-and-pharmacodynamic-poppk-pd-modeling-to-support-revised-dose-dosing-regimens-dose-mitigation-scheme/. Accessed December 5, 2021.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/fitusiran-population-pharmacokinetic-and-pharmacodynamic-poppk-pd-modeling-to-support-revised-dose-dosing-regimens-dose-mitigation-scheme/