Antithrombin lowering in hemophilia: a closer look at fitusiran

Abstract

Thrombin is a key enzyme in the maintenance of normal hemostatic function and is the central product of an interconnected set of simultaneously occurring cellular and proteolytic events. Antithrombin (AT) is a natural anticoagulant that downregulates different components of the clotting process, particularly thrombin generation. In good health, well-regulated hemostasis is the result of a balance between procoagulant and anticoagulant elements. Cumulative understanding of the regulation of thrombin generation and its central role in hemostasis and bleeding disorders has led to the clinical development of therapeutic strategies that aim to rebalance hemostasis in individuals with hemophilia and other coagulation factor deficiencies to improve bleeding phenotype. The aim of this review is to discuss the rationale for AT lowering in individuals with hemophilia, with a focus on fitusiran, its mechanism of action, and its potential as a prophylactic therapy for individuals with hemophilia A or B, with or without inhibitors. Fitusiran is an investigational small, interfering RNA therapeutic that targets and lowers AT. It is currently in phase III clinical trials and results have shown its potential to increase thrombin generation, leading to enhanced hemostasis and improved quality of life while reducing the overall treatment burden.

Keywords: antithrombin; fitusiran; hemophilia; small interfering RNA; thrombin.

Graphical abstract

Figure 1

The cell-based model of initiation (1), amplification (2), and propagation (3) leading to coagulation. FV, factor V; FVa, activated factor V; FVIIa, activated factor VII; FVII; factor VII; FVIII, factor VIII; FIX, factor IX; FIXa, activated factor IX; TF, tissue factor; vWF, von Willebrand factor.

Figure 2

The role of thrombin and antithrombin in hemostasis, and the mechanism of action of fitusiran. EPCR, endothelial cell protein C receptor; FII, factor II; FIIa, activated factor II; FV, factor V; FVa, activated factor V; FVII, factor VII; FVIIa, activated factor VII; FVIII, factor VIII; FVIIIa, activated factor VIII; FIX, factor IX; FIXa, activated factor IX; FX, factor X; FXa, activated factor X; FXI, factor XI; FXIa, activated factor XI; FXIII, factor XIII; FXIIIa, activated factor XIII; Protein Ca, activated protein C; TAFI, thrombin activatable fibrinolysis inhibitor; TF, tissue factor; TM, thrombomodulin.

Figure 3

Key dates in the chronology of the fitusiran clinical development program. The black dashed lines indicate study initiation. The black solid lines indicate study completion.

Figure 4

Effect of fitusiran on antithrombin activity in phase I study in people with hemophilia with inhibitors. (A) Phase I Part C. (B) Phase I Part D. (A) The arrows below the graph indicate the timing of the injections. The I bars represent standard errors, which were calculated only for cohorts with at least two participants. Source: Reproduced with permission from Pasi et al. [32]. (B) MDI, multiple doses with inhibitor; SEM, standard error of mean [39]. Source: Reproduced with permission from Pasi et al. [39].

Figure 5

Fitusiran revised dose and dose regimen, targeting an antithrombin range from 15% to 35% [62]. The revised dose and dose regimen was introduced as of December 2020. BPA, bypassing agent; CFC, clotting factor concentrate; Q2M, every other month; SS, steady state. Source: Figure adapted with permission from Pipe et al. [62]. ^aParticipants are eligible for dose escalation if >4 doses of fitusiran have been administered at the current dose level, and they experienced >2 predose antithrombin (AT) activity levels >35% (as per central laboratory) after their second dose at the current dose, and fitusiran administration and AT activity assessments occurred as per schedule at the current dose level. ^bParticipants previously escalated to a dose of 20 mg every month (QM), 50 mg QM or 80 mg QM due to AT >35% who experience >1 AT activity level <15% within a 12 month period must either permanently discontinue fitusiran prophylaxis, or in consultation with the Study Medical Manager may have the option to be de-escalated to their prior dose level. ^cStart of dosing after de-escalation from higher dose to occur only after centrally measured AT levels ≥22%. Participants receiving fitusiran at a dose of 20 mg every other month who experience ≥1 AT activity level <15% (as per central laboratory) within a 12-month period must permanently discontinue fitusiran treatment. ^dParticipants with QM dosing bleeding episodes during the first 8 weeks at the current dose level or every other month dosing bleeding episodes during the first 12 weeks at the current dose level will not be considered for this judgment.