Background Hemophilia A (HB) and B (HB) are rare, inherited bleeding disorders characterized by a deficiency of clotting factors VIII or IX, respectively, leading to recurrent spontaneous and trauma-related bleeding. While prophylactic treatment with factor concentrates or mimetics significantly reduces bleeding and improves outcomes, these therapies often require frequent administration or can cause injection-site discomfort, making patient compliance challenging. Suboptimal compliance increases risks of bleeding, joint damage, hospitalization, and healthcare costs.

Fitusiran is an antithrombin (AT)-lowering therapeutic that increases thrombin generation to restore hemostasis in people with hemophilia A/B (PwHA/B), with or without inhibitors. In the Phase 3 ATLAS-OLE study (NCT03754790), designed to investigate the safety and efficacy of the fitusiran AT-based dose regimen (AT-DR) targeting AT levels between 15–35%, meaningful bleed protection was maintained in PwH. Here we report the participant experience with fitusiran treatment in relation to compliance, tolerability and common adverse events (AEs) on the AT-DR.

Methods In ATLAS-OLE, males aged ≥12 years with severe hemophilia A or B, with or without inhibitors received the fitusiran AT-DR (starting dose 50 mg once every 2 months [Q2M]). The primary endpoint was safety and tolerability. Safety endpoints included incidence, severity, seriousness, and relatedness of AEs. Analyses of compliance, tolerability, and common treatment-emergent adverse events (TEAEs) for all participants who received ≥1 dose of fitusiran on the AT-DR were summarized descriptively. Treatment compliance was calculated as the total dose received as a percentage of the total dose expected to be received under the AT-DR. Mean compliance was calculated from the total number of participants who received AT-DR during the study.

Results A total of 213 participants received the fitusiran AT-DR (n=56 HA with inhibitor; n=106 HA without inhibitor; n=19 HB with inhibitor; n=32 HB without inhibitor) during the ATLAS-OLE trial with 94% requiring 0–1 dose adjustment to achieve target AT levels. Overall, 166 (78%) participants receiving AT-DR were on Q2M regimens. The overall mean compliance with fitusiran AT-DR was 96.0%, with comparable results between participants with HA (95.7%) and HB (96.6%), and between participants without inhibitors (96.6%) and with inhibitors (94.7%). A total of 158 (74.2%) participants demonstrated 100% compliance, and the proportions were also comparable between participants with HA (75.3%) and HB (70.6%), and between the non-inhibitor (73.9%) and inhibitor participants (74.7%). Of 39 (18.3%) participants that discontinued during the AT-DR, 30 (14.1%) were due to >1 AT measurement <15%, 5 (2.3%) due to adverse events (hepatocellular carcinoma, transaminase elevation, cerebral infarction, pruritus, and postoperative deep-vein thrombosis), 3 (1.4%) due to withdrawal of consent, and 1 (0.5%) due to 'other’.

With the AT-DR, the most commonly reported (≥10% of participants) TEAEs were infections (n=93 [43.7%] participants), of which COVID-19 (n=25 [11.7%] participants) was the most common AE. Other common TEAEs included gastrointestinal disorders (n=65 [30.5%]), nervous system disorders (n=34 [16%]), and musculoskeletal and connective tissue disorders (n=67 [31.5%]), of which arthralgia (n=22 [10.3%]) was the most common AE.

ConclusionsThis analysis confirms that in participants receiving the AT-DR, fitusiran was associated with high overall levels of compliance (96.0%) and was well tolerated as demonstrated by low discontinuation rates due to AEs (2.3%). The high treatment compliance observed in ATLAS-OLE is likely due to reduced treatment burden afforded by the Q2M regimens (that 78% of participants were receiving), supporting the clinical utility of fitusiran in PwHA or B, with or without inhibitors.

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2025
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