Fitusiran
With demonstrated efficacy in phase 3 trials for both hemophilia A and B regardless of inhibitor status, fitusiran has the potential to be a transformative therapy for all people with hemophilia. A small interfering RNA (siRNA) therapy, fitusiran works by inhibiting and degrading SerpinPC1 mRNA, which reduces antithrombin levels. This promotes thrombin generation, rebalances hemostasis and prevents bleeds. Fitusiran uses Alnylam Pharmaceutical Inc’s ESC-GalNAc conjugate technology and, depending on the approval timeline, could be a first-in-class antithrombin-lowering therapy based on a double-stranded RNA molecule.
About Fitusiran
- Alnylam Pharmaceuticals Inc and Sanofi
- Antithrombin-targeting siRNA
- Subcutaneous administration once monthly or bimonthly for prophylactic treatment of hemophilia A or B with or without inhibitors
- ~45K diagnosed prevalent cases of hemophilia A in the G7 markets in 2023
- ~11K diagnosed prevalent cases of hemophilia B in the G7 markets in 2023
Why is it a drug to watch?
Data from completed phase 3 trials indicate that prophylaxis treatment with fitusiran results in significant reductions in the annualized bleeding rate (ABR), compared with on-demand factor concentrate, and no bleeding events in approximately one-half of participants. Also, it enables the safe execution of major surgeries in individuals with hemophilia A or B with or without inhibitors. Additional safety data have emerged from studies using an antithrombin-based dosing regimen (AT-DR), which was adopted in 2021 when trials resumed after a pause in late 2020 due to safety concerns. With AT-DR, fitusiran effectively mitigates the risk of thrombotic events and reduces the incidence of elevated liver enzymes, gallbladder inflammation and gallstones.
The efficacy and safety of fitusiran are being investigated in the ATLAS clinical development program, with results reported from the following completed phase 3 studies:
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ATLAS-A/B study with 120 participants (≥12 years old) with hemophilia A or B without inhibitors
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Once-monthly prophylactic SC fitusiran administration for 9 months vs on-demand factor concentrate
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89.9% reduction in treated ABR in the fitusiran group .
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Median ABR: 0.0 (fitusiran) vs 21.8 (on-demand factor concentrate)
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0 treat bleeds: 50.6% (fitusiran) vs 5.0% (on-demand factor concentrate)
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TEAEs of interest with fitusiran were any alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation (>3x upper limit of normal), reported for 19% of the fitusiran group
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ATLAS-INH study with 60 participants (≥12 years old) with hemophilia A or B with inhibitors
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Once-monthly prophylactic SC fitusiran administration for 9 months vs on-demand bypass agent
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90.8% reduction in treated ABR in the fitusiran group.
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Median ABR: 0.0 (fitusiran) vs 16.8 (on-demand bypass agent)
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25 patients (65.8%) treated with fitusiran: no bleeding events
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TEAEs of special interest of any ALT or AST elevation (>3x upper limit of normal) and suspected, or confirmed thromboembolism were reported in the fitusiran arm in 10 patients (24.4%)
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ATLAS-PPX study with 80 patients (≥12 years old) with severe hemophilia A or B with or without inhibitors previously treated prophylactically with a factor or bypass agent
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Once-monthly prophylactic SC fitusiran administration for 7 months (prior treatment as comparator)
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ABR for all bleeds: 2.9 (fitusiran) vs 7.5 (prior factor concentrate or bypass agent prophylaxis)
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Spontaneous bleeds: 2.2 (fitusiran) vs 5.0 (prior factor concentrate or bypass agent prophylaxis)
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No bleeding events: 44 (67.7%; fitusiran) vs 22 (33.8%; prior factor concentrate or bypass agent prophylaxis)
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SAEs: 9 (13.4%; fitusiran) vs 5 (7.7%; prior factor or bypass agent prophylaxis)
The following trials are ongoing:
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ATLAS-OLE: open-label extension study for ATLAS-A/B, ATLAS-INH and ATLAS-PPX
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281 participants (≥12 years old) with severe hemophilia A or B with or without inhibitors
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Once-monthly or bimonthly prophylactic SC fitusiran administration using the AT-DR, which was designed to maintain an antithrombin target range of 15%-35% (lower doses, less frequent dosing) for up to 48 months
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Primary endpoint: number of participants with TEAEs
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Secondary endpoint: ABR plus three
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Estimated completion: November 2026
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Phase 3 ATLAS-PEDS: dose-finding study
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32 children (1 year to <12 years old) with hemophilia A or B with or without inhibitors
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SC fitusiran administration for 256 weeks
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Primary endpoint: plasma antithrombin activity levels
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Estimated completion: August 2028
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Phase 3 ATLAS-NEO
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75 male participants (≥12 years old) with severe hemophilia A or B with or without inhibitors previously treated with SOC
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SOC (clotting factor concentrate or bypass agent; antithrombin concentrate [ATIIIC]) for six months, SC fitusiran using the AT-DR for 36 months, anthithrombin follow-up for six months
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Primary endpoint: ABR
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Estimated completion: March 2028
Review and approval status
July 2014
Orphan designation: EMA (hemophilia A)
February 2021
Fast track status granted: U.S. FDA
December 2023
Breakthrough Therapy Designation (hemophilia B with inhibitors): U.S. FDA
May 2024
MAH submitted: Mainland China NMPA
June 2024
NDA accepted: U.S. FDA
March 28, 2025
PDUFA date
Actual and expected launch:
- 2025: European Union, Japan, Mainland China, United Kingdom, United States
Patents estimated to expire beginning in 2022
Drug Timeline & Success Rates
Source: Cortellis Competitive Intelligence, Drug Timeline & Success Rates Prediction current as of October 31, 2024
How will fitusiran impact the market for hemophilia A and B?
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With the introduction of multiple non-factor and gene therapies over the next four to five years, the treatment paradigm for hemophilia B is expected to significantly evolve, and clinicians will have multiple effective, convenient options for all patients with hemophilia.
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Hemostatic-rebalancing, non-factor therapies, including fitusiran, Alhemo™ (concizumab; Novo Nordisk) and HYMPAVZI™ (marstacimab; Pfizer Inc), could be a more convenient option than factor concentrates for hemophilia B without inhibitors. However, extended half-life FIX therapies have similar efficacy and safety and a low dosing burden and could be the treatment of choice for patients who are already well managed on them. With HEMLIBRA® (emicizumab; Genentech, a member of the Roche Group, and Chugai Pharmaceutical Co Ltd) and now ALTUVOCT®/ALTUVIIIO® (Sobi® and Sanofi), patients with hemophilia A have the option of once-weekly non-factor or factor dosing. Therefore, emerging therapies without a distinct efficacy or safety advantage and a similar dosing burden are not expected to overtake established therapies.
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The SC route of administration and less frequent dosing of fitusiran and HYMPAVZI will likely encourage treatment switching among the treated population. This will be important for market share since drug treatment rates are high and there is limited scope to increase them. In fact, the overall market is expected to grow very slowly over the next decade.
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The use of on-demand bypass agents like NovoSeven® (Novo Nordisk), FEIBA (Takeda) and SEVENFACT® (HEMA Biologics), which have a high injection burden and lower efficacy against bleeds, is expected to decline as patients shift to non-factor and gene therapies such as HEMGENIX® (etranacogene dezaparvovec; CSL Behring) and BEQVEZ™ (fidanacogene elaparvovec; Pfizer Inc) that offer better clinical profiles, similar safety, greater convenience and lower cost (in the case of non-factor therapies).
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Fitusiran is expected to have a significant impact on all four markets (hemophilia A and B with or without inhibitors):
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The largest impact will likely be for individuals with hemophilia B with inhibitors.
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For hemophilia A, fitusiran’s similar risk-benefit profile and monthly/bimonthly administration might provide an advantage over HEMLIBRA, which is shifting toward once-weekly injections, according to KOLs. This indicates that once-monthly administration might be less clinically efficacious.
What gaps in treatment does fitusiran fill?
A primary goal in the treatment of hemophilia A and B is to prevent bleeding, particularly bleeding into the joints, which is associated with permanent joint damage. Another important outcome is improved quality of life. However, the route of administration (i.e., intravenous) for current FVIII and FIX replacement therapies and dosing frequency (once or twice a week) of current FVIII replacement therapies are burdensome, increase the risk of infections and thrombosis and contribute to suboptimal compliance rates. As a subcutaneously infused therapy once a month or once every two months, fitusiran could improve patient convenience, reduce the treatment burden and enhance treatment compliance. In addition, 20-30% of patients treated with replacement therapies will develop inhibitors at some point, but treatments are limited for this population, increasing disease-related morbidity and mortality. Fitusiran could help fill that gap.
What hurdles might it need to overcome to reach blockbuster status?
Fitusiran is entering a highly competitive market, with a fairly narrow patient population and well-established prophylactic and on-demand treatment options with which both patients and clinicians are familiar. Some treatments, like ALTUVOCT/ALTUVIIIO, Elocta®/Eloctate® (Sobi and Sanofi), ADYNOVATE® (Takeda) and HEMLIBRA for hemophilia A and IDELVION® (CSL Behring) for hemophilia B, also have more convenient dosing schedules than standard half-life and extended half-life therapies. Therefore, switching to another treatment might not be as attractive for patients already being managed on those drugs. In the non-inhibitor population, many patients are well managed on factor concentrates, which could make it challenging for new non-factor therapies to have an impact. Clinician concerns about safety, such as occurrence of thrombotic events, could also limit the initial uptake of fitusiran, at least until sufficient real-world data are collected.
