Fitusiran Population Pharmacokinetic and Pharmacodynamic Modeling Utilizing Phase 3 Clinical Trial Data to Confirm Doses Tested in Phase 3 Trials to Support an Antithrombin-Based Dose Regimen

Background:

Fitusiran is an investigational siRNA therapeutic designed to target antithrombin (AT) with the goal of rebalancing hemostasis in people with hemophilia (PwH) A or B, regardless of inhibitor status. A semi-mechanistic population pharmacokinetic/pharmacodynamic (PopPK/PD) model using Phase 1/2 data from 1000 virtual PwH was previously developed to inform dose selection for the Phase 3 program using a fitusiran AT-based dosing regimen. This indicated that a starting dose of 50 mg once every 2 months (Q2M) would maintain AT activity between 15–35% for a considerable number of PwH, and aim to mitigate the risk of thrombosis and preserve bleed control. This analysis presents an updated fitusiran PopPK/PD model using pooled Phase 1/2 and Phase 3 AT activity data to guide an AT-based dose regimen for Phase 3 trials in adults with hemophilia.

Methods:

Plasma AT activity data from Phase 1 (NCT02035605), Phase 1/2 (NCT02554773) and Phase 3 studies (NCT03417102, NCT03417245, NCT03549871) in PwH A/B, with or without inhibitors were pooled to update the PopPK/PD model. Pooled AT activity data generated a large dataset with diverse populations and allowed for the evaluation of potential effects of intrinsic and/or extrinsic factors as covariates on AT activity in the targeted hemophilia population. The final PopPK/PD model was used to simulate AT activity at various dosing regimens in 1500 virtual PwH to select the final AT-based dosing regimen.

Results:

The PopPK/PD dataset included 44059 AT activity observations from 339 participants. An indirect response model (Figure 1) well described the dynamics of AT activity and intra-individual variability. The covariate effects identified in the PopPK/PD model were White race on Kout (increase in elimination rate of AT) and half maximal inhibitory concentration (IC50; increase in model derived potency estimate), bodyweight on Kout (increase with bodyweight), age with IC50 (increase with age). Simulations predict that with a starting dose of 50 mg Q2M, >58% of PwH would achieve AT activity >15% (10^th percentile trough-AT activity was 15.3%). Mean peak AT activity is projected to be 24.7 ± 10%. For PwH with >35% AT activity, a dose escalation to 50 mg every month (QM) would be required to achieve target AT activity <35%. It is predicted that 0.8% of PwH would then be escalated to 80mg QM in a stepwise manner. With the starting dose of 50 mg Q2M, 41.7% of PwH are predicted to have AT activity <15%; these PwH should be de-escalated to 20 mg Q2M. At a dose of 20 mg Q2M, 10.2% would have AT activity <15% (Figure 2).

Conclusions:

PopPK/PD model simulations confirm that the fitusiran AT-based dose regimen with a starting dose of 50 mg Q2M that can be escalated or de-escalated maintains the target AT range of 15–35% in the majority of PwH. It is predicted approximately 88% of PwH will require zero or one dose change. The efficacy and safety of the fitusiran AT-based dose regimen is being evaluated in ongoing clinical trials.