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Abstract Introduction Fitusiran is an antithrombin (AT)-lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia A or B (PwHA/B), with or without inhibitors. In an ongoing, multicenter, multinational, Phase 3 open-label extension study (ATLAS-OLE; NCT03754790), the fitusiran antithrombin-based dose regimen (AT-DR) targeting AT levels of 15–35% was developed to optimize the benefit-risk profile at the lower bound and the efficacy at the upper bound of AT knockdown. In ATLAS-OLE, the AT-DR was well tolerated and maintained clinically meaningful bleed protection with a median (interquartile range) observed annualized bleeding rate of 3.7 (0.0, 7.5). However, 11.7% of participants discontinued fitusiran due to persistent AT levels <15% on the lowest dose (20 mg once every two months [Q2M]) in accordance with the study protocol, despite adequate bleed control and no safety concerns. After regulatory review, an additional lower dose of 10 mg was introduced to allow more patients to remain on fitusiran. Here we describe the rationale for the approval of the new, lower fitusiran dose (10 mg Q2M and once monthly [QM]). Methods The doses that comprised the AT-DR (50 mg Q2M starting dose, 20 mg Q2M/QM, and 80 mg QM depending on steady state AT levels) were validated using a population semi-mechanistic model(Madrasi et al, ASH 2023. Poster number 2614) which simulated participant distribution across AT-DR doses that were comparable to observed data in ATLAS-OLE. In this analysis, similar simulations were used to identify a lower dose (10 mg Q2M/QM or 15 mg QM) that may provide an additional dosing option for participants reporting AT levels <15% on the 20 mg Q2M dose, increase the proportion of patients within the target AT activity range, and reduce the number of fitusiran discontinuations. Results Population modelling was based on 1358 simulated participants and utilized observed clinical data from 283 participants in the ATLAS-OLE study. With the AT-DR, simulations predicted that 6.7% of participants were expected to discontinue fitusiran due to <15% AT levels on the 20 mg Q2M dose. Simulations of 10 mg Q2M and 15 mg QM dose regimens predicted 0.96% and 2.8% of participants would have AT levels <15%, respectively. The addition of fitusiran 10 mg Q2M and QM dose regimens to the model resulted in 0.66% of simulated participants that would need to discontinue treatment while on AT-DR due to AT levels <15%. Conclusions Fitusiran 10 mg Q2M and QM doses were approved by the FDA based on modeling and simulation data. These additional dose regimens may result in fewer than 1% of participants discontinuing fitusiran due to AT levels <15%. Overall, these findings are the basis for the FDAs decision to include the lower dose of fitusiran to benefit a broader population with hemophilia A or B, regardless of inhibitor status. Real-world data collection of participants receiving AT-DR will further aid understanding of the effects of this lower fitusiran dose.