Fitusiran, approved under the brand name Qfitlia, is an RNA interference (RNAi) therapeutic developed by Sanofi in collaboration with Alnylam Pharmaceuticals. This therapy offers a new approach to managing hemophilia A or B, genetic bleeding disorders caused by a deficiency of clotting factor VIII or IX. Traditional treatment relies on replacing the missing factor, often requiring frequent intravenous infusions. Qfitlia uses a novel mechanism to promote clotting, addressing the need for less burdensome prophylactic options. This review details Qfitlia’s role, mechanism of action, regulatory path, and associated safety measures.
The Role of Fitusiran in Hemophilia Treatment
Qfitlia is indicated for routine prophylaxis, meaning it is used to prevent or reduce the frequency of bleeding episodes, in patients aged 12 years and older. It covers both hemophilia A and hemophilia B, and is approved for use regardless of whether patients have developed inhibitors. Inhibitors are neutralizing antibodies that render traditional factor replacement therapies ineffective.
Patients with inhibitors have a high unmet medical need, as standard factor replacement is not viable. Their management typically involves bypassing agents, which can be less predictable. Qfitlia offers a prophylactic option that is mechanistically independent of the deficient factor, providing an alternative for this challenging group.
Unlike conventional factor replacement therapies, Qfitlia rebalances the patient’s intrinsic clotting system to provide consistent bleed protection. It is administered via a subcutaneous injection, which is simpler than the intravenous infusions required for most factor products. The approved regimen allows for dosing as infrequently as once every two months, substantially reducing the annual treatment burden.
Mechanism of Action: Targeting Antithrombin
Qfitlia is an antithrombin (AT)-directed small interfering ribonucleic acid (siRNA) therapeutic. It utilizes RNA interference, a natural biological process, to specifically target and silence the gene responsible for producing antithrombin. The siRNA molecule is engineered to travel to the liver, where AT is synthesized.
Inside the liver cells, Qfitlia binds to the messenger RNA (mRNA) carrying the genetic instructions for antithrombin. This binding prevents the mRNA from being translated, reducing the amount of AT circulating in the bloodstream. Since antithrombin acts as a major physiological inhibitor of blood clotting, lowering its concentration shifts the balance of the coagulation cascade.
Reducing AT diminishes the natural braking mechanism on clotting. This allows for increased generation of thrombin, which is essential for forming a stable blood clot. By promoting sufficient thrombin generation, Qfitlia compensates for the deficiency in factor VIII or IX, restoring hemostasis even when factor levels are low.
Regulatory Journey and Current Approval Status
The U.S. Food and Drug Administration (FDA) approved Qfitlia for routine prophylactic use on March 28, 2025. This approval was based on data from the Phase 3 ATLAS clinical development program, which evaluated the therapy’s safety and efficacy across different hemophilia populations. The program demonstrated that Qfitlia prophylaxis provided clinically meaningful bleed protection, measured by a reduction in the Annualized Bleeding Rate (ABR).
The studies showed significant ABR reduction compared to those receiving on-demand treatment. For participants with inhibitors, the antithrombin-based dosing regimen (AT-DR) resulted in a 73% reduction in estimated ABR compared to on-demand bypassing agents. In patients without inhibitors, the reduction was 71% compared to those on-demand clotting factor concentrates.
The regulatory process faced challenges, including voluntary dosing pauses due to reports of non-fatal thrombotic events. To address these safety concerns, the sponsor revised the protocol, adopting the antithrombin-based dose regimen (AT-DR).
This revised regimen shifted the focus from a fixed monthly dose to one adjusted based on a patient’s monitored antithrombin levels. The FDA decision to approve Qfitlia recognizes this successful mitigation strategy, which allowed the therapy to move forward as a new option for adults and adolescents. The FDA had previously granted the therapy Orphan Drug, Fast Track, and Breakthrough Therapy designations, highlighting its potential to address an important need in hemophilia care.
Understanding the Safety Profile and Risk Management
The most serious adverse event associated with Qfitlia is the risk of thrombotic events (blood clots), which led to clinical holds and protocol revisions. This risk stems from the drug’s mechanism: excessive suppression of antithrombin can cause an overly procoagulant state, especially if AT levels fall below 10% of normal. The initial fixed-dose regimen carried a higher risk of these events.
The approved AT-DR regimen manages this risk by mandating that a patient’s antithrombin activity level be maintained within a target range of 15% to 35%. Dosing and frequency are adjusted based on monitoring, potentially allowing injections as infrequently as once every two months. The FDA-cleared INNOVANCE Antithrombin assay must be used to monitor AT activity and inform dosing decisions.
Safety information also includes warnings regarding acute and recurrent gallbladder disease, such as cholelithiasis and cholecystitis. Hepatotoxicity, indicated by elevated liver enzymes, has also been reported. This requires monitoring liver function tests at baseline and monthly for at least six months after starting treatment or increasing the dose.
Management of breakthrough bleeding episodes requires caution. Because Qfitlia makes the blood more procoagulant, traditional clotting factor concentrates or bypassing agents must be used at substantially reduced doses compared to standard practice. Specific guidelines have been established to prevent the combination of AT suppression and high doses of procoagulants from triggering a thrombotic event.