Fitusiran Achieves Sustained Antithrombin Activity Regardless of Dose with Steven Pipe, MD

A review of clinical and population data from the ATLAS-OLE trial has characterized the pharmacokinetics and pharmacodynamics of fitusiran in patients with hemophilia A or B, using dose guidance provided by a Population Pharmacokinetic-Pharmacodynamic (PopK-PD) model. Fitusiran achieved steady-state antithrombin activity (AT) within the 15-35% target range with 0 to 1 dose changes in most patients.

Fitusiran is a subcutaneous small interfering RNA therapeutic targeting antithrombin to rebalance homeostasis in patients with hemophilia A or B. It was officially approved by the US Food and Drug Administration (FDA) in March 2025.1

ATLAS-OLE is an interventional phase 3 trial. Begun in January of 2019, ATLAS-OLE is still ongoing and is expected to end in November of 2026. Patients received fitusiran AT-DR 50 mg either monthly or every two months, and were adjusted to 20 mg if a change was needed based on AT levels. A total of 17,358 samples were collected from 339 participants for the clinical and population data review. Investigators conducted simulations on these samples using a PopK-PD model, which was developed using data pooled from prior phase 1/2/3 studies. The study aimed to maintain AT levels between 15 and 35%.2

Ultimately, these simulations predicted that >99% of participants will reach steady-state AT within 19.9 to 22.7 weeks following initiation of fitusiran, regardless of dose regimen. These results are consistent with clinical observations. Additionally, following discontinuation of fitusiran, AT activity was projected to remain <60% for roughly 20 weeks. Covariates such as weight had no significant effect on the model parameters.3

A collective 80 participants (37.6%) required no dose changes, 120 (56.3%) required 1 dose change, and 13 (6.1%) required >1 dose change to achieve AT activity 15-35%. Median time to reach final dose was 111 days (interquartile range, 0; 280).3

Steven Pipe, MD, professor of pathology and Laurence A. Boxer Research Professor of Pediatrics at the University of Michigan, sat down with HCPLive to discuss the results of the review and the implications for hematology at large.

“What really impressed me as we went through this population PK and pharmacodynamic assessment is how many patients are going to be fine on the starting dose of 50 mg every other month and will not require any dose changes,” Pipe told HCPLive. “And if you do a dose change, it’s most likely that you would actually do a dose change to a lower dose.”

Pipe also explained the impact these data may have on the future of hemophilia A and B treatment.

“This is really going to realize an effective prophylactic regimen for patients with just six subcutaneous doses a year,” Pipe said. “And then, on the edges, there may be patients that need a monthly regimen, or might need some additional monitoring.”

Pipe noted the convenience and easy transportability of the proposed pen delivery device, which, based on these findings, will be fixed at 50 mg per dose.

“The other thing about the delivery of this device that I think is going to be attractive to patients is that it comes in a prefilled syringe,” Pipe continued. “It’s basically a pen, if you like, and the 50 mg, which is going to be the predominant dose that people are on, will be the fixed syringe. And this has long stability at room temperature for several months. It’s going to make it easy for people to travel if they need to bring it with them.”

Editors’ Note: Pipe reports disclosures with Siemens, Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, Bayer, Biomarin, and others.

References

1. Kenet G, Nolan B, Zulfikar B, et al. Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial. Blood. 2024;143(22):2256-2269. doi:10.1182/blood.2023021864

2. Long-term Safety and Efficacy Study of Fitusiran in Patients With Hemophilia A or B, With or Without Inhibitory Antibodies to Factor VIII or IX (ATLAS-OLE). ClinicalTrials.gov identifier: NCT03754790. Updated July 15, 2024. Accessed July 23, 2025. https://clinicaltrials.gov/study/NCT03754790

3. Pharmacodynamics and pharmacokinetics of fitusiran antithrombin-based dose regimen (AT-DR): clinical and population modeling data. Presented at the 2025 International Society for Thrombosis and Heamostasis Congress in Washington, DC, June 21-25, 2025.