CME
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: March 01, 2022
Expiration: February 28, 2023
Sujit Sheth, MD:
Hemophilia A and B are inherited bleeding disorders that are characterized by a missing or dysfunctional protein—factor VIII for hemophilia A and factor IX for hemophilia B—and the standard of care of treatment currently is to replace the missing factor.16 Some novel nonfactor therapies for hemophilia A have been studied, including bispecific antibodies like emicizumab, which we should keep in mind as we talk about this novel agent.
Approximately 30% of patients with hemophilia A and 5% of patients with hemophilia B will develop an inhibitor, which is a neutralizing antibody that clears infused factor within seconds and therefore does not allow the replacement factor to work.17-20 The development of an inhibitor is associated with a significant bleeding phenotype, a much worse prognosis, and a higher rate of mortality.
At ASH 2021, Young and colleagues21 presented data from the randomized phase III ATLAS-INH trial of fitusiran, an antithrombin-directed siRNA therapeutic that aims to restore thrombin production and rebalance hemostasis, in patients with hemophilia A or B with inhibitors.22
Fitusiran 80-mg was administered subcutaneously once per month along with on-demand bypassing agent (BPA) vs on-demand BPA therapy alone. The primary endpoint was the annualized bleeding rate (ABR) during the efficacy period. Secondary endpoints included spontaneous ABR, joint ABR, frequency of bleeding episodes during the onset period, safety and tolerability, and quality of life (QoL) that is an important consideration for this patient population.
Sujit Sheth, MD:
Most baseline characteristics were well balanced between the fitusiran group and the control group. Of note, in the fitusiran group vs the control group, 64% vs 36% of patients had hemophilia type A and 75% vs 25% had hemophilia type B.
Sujit Sheth, MD:
The median ABR was significantly lower in the fitusiran group vs the control group (0.0 vs 16.8; P <.0001), as was the median ABR for spontaneous bleeds (0.0 vs 13.4; P <.0001), and the estimated mean ABR (1.7 vs 18.1; P <.0001). Furthermore, the number of patients not treated for bleeds was significantly higher in the fitusiran group vs the control group (25 vs 1; P <.0001). Finally, QoL measures favored the fitusiran group vs the control group, as shown by reductions from baseline in the hemophilia QoL questionnaire for adults.
Sujit Sheth, MD:
Compared with the control group, patients receiving fitusiran experienced a significant reduction in median ABR regardless of the hemophilia subtype; median ABR was 0.0 vs 15.9 (P <.0001) in patients with hemophilia A; and median ABR was 1.7 vs 18.4 (P <.0001) in patients with hemophilia B.
Sujit Sheth, MD:
Treatment-emergent AEs were higher in the fitusiran group compared with the control group (92.7% vs 57.9%). Regarding treatment-emergent AEs of special interest, investigators observed elevation in liver enzymes and cholestasis in the fitusiran group but not in the control group. These changes were therefore likely related to the drug itself. Finally, thromboembolic events, which are a significant concern for an agent that increases thrombin generation, were observed at a higher rate in the fitusiran group compared with the control group (deep vein thrombosis: 2.4% vs 0.0%; subclavian vein thrombosis: 2.4% vs 0.0%; thrombophlebitis superficial: 2.4% vs 0.0%; thrombosis: 2.4% vs 0.0%). It should be noted, however, that three of these events occurred in a single patient.
Sujit Sheth, MD:
The investigators therefore concluded from these data that fitusiran prophylaxis dosed at 80 mg subcutaneously once per month reduced the rate of bleeding among individuals with hemophilia A or B with inhibitors. Furthermore, improvements in QoL were observed, and the reported treatment-emergent AEs were consistent with previous reports in patients with hemophilia A or B with inhibitors.
These data are encouraging for patients with hemophilia B with inhibitors, particularly because we may finally have a drug that is able to prophylactically provide a constant level of hemostatic activity in patients who otherwise would be very prone to bleeding and for whom we currently do not have a good prophylactic regimen. Patients with hemophilia A with inhibitors can be treated with emicizumab and the benefit appears to be similar to that of fitusiran in this study. Of importance, emicizumab is not effective in patients with hemophilia B because there is no circulating factor IX.
Sujit Sheth, MD:
The phase III ATLAS-A/B study is investigating fitusiran in patients with hemophilia A and B without inhibitors.23 In this study, investigators studied fitusiran 80 mg subcutaneously as prophylaxis once monthly along with on-demand use of factor replacement therapy (FRT) for breakthrough bleeding episodes vs on-demand use of FRT for breakthrough bleeding episodes alone. This design is therefore different than that of the prior study because a prophylaxis for patients with hemophilia B with inhibitors doesn’t exist. In that study, it was appropriate to compare patients with on-demand therapy for bleeding episodes with a novel agent that would provide a prophylactic regimen. Here, however, fitusiran is being used as a prophylactic agent, and it therefore should be compared with therapy for patients who are on prophylaxis as well, not with patients who received on-demand therapy. In my opinion, this comparison is not the most appropriate.
Nevertheless, the primary endpoint of the study was ABR. Secondary endpoints were the annualized joint bleeding rate, health-related QoL, safety, and tolerability.
Sujit Sheth, MD:
As in the previous trial, baseline characteristics were well balanced between the treatment arms. Mean age was 3.8 years; most patients had hemophilia A (77.5%), and mean bleeding episodes in the 6 months prior to screening was approximately 12.
Sujit Sheth, MD:
Regarding bleeds requiring treatment during the efficacy period, the rate was significantly lower with fitusiran prophylaxis vs the on-demand FRT (median ABR: 0 vs 21.8; P <.0001). Improvements were also observed for fitusiran vs the on-demand FRT in median ABR for treated joint bleeds (0 vs 15.9; P <.0001) and treated bleeds (0 treated bleeds: 50.6% vs 5.0%; ≤3 treated bleeds: 83.5% vs 15.0%). These results were expected because it is known that patients who receive prophylaxis will have a decreased number of bleeds. If fitusiran prophylaxis had been compared with another prophylaxis, the results may have been different, but this was not the trial design.
Sujit Sheth, MD:
Quality of life scores favored the fitusiran arm vs the on-demand FRT arm. The mean change in the Hemophilia Quality of Life Questionnaire for Adults was significantly improved from baseline to end-of-study for the fitusiran arm vs on-demand FRT arm (total score: -9.68 vs -2.62; P = .0011; physical health score: -23.07 vs -3.32; P <.0001). This also was expected because patients were bleeding much less with fitusiran treatment.
Sujit Sheth, MD:
Treatment-emergent AEs with fitusiran were mostly related to hepatic irritation. Compared with the on-demand FRT arm, patients in the fitusiran arm had notable elevation in liver enzymes (19.0% vs 2.5%). Of interest, patients in the ATLAS-A/B study did not develop thrombosis. It is well known that patients who have inhibitors, although highly prone to bleeding, can potentially enter a prothrombotic state when using a bypassing agent combined with fitusiran, which also increases thrombin generation. This was not dissimilar to what we saw in the initial trials with emicizumab and bypassing agents where an increased rate of thrombosis and microvascular thrombosis was observed.24 Thus, these results were expected, and it is reassuring to see that thrombosis does not appear to be a concern in patients without inhibitors receiving treatment with fitusiran.
Sujit Sheth, MD:
The investigators of the trial concluded that prophylaxis with fitusiran showed a significant reduction in ABR for patients with severe hemophilia A or B without inhibitors. As mentioned previously, this was not surprising because prophylaxis was compared with on-demand therapy. Reductions in bleeding episodes translated into meaningful improvements in QoL.
Regarding utilization, emicizumab is already an established therapy for patients with hemophilia A, and most patients who would be eligible already have been switched over to it. Therefore, there would likely be limited uptake of fitusiran in patients with hemophilia A. For patients with hemophilia B, there is an unmet need for a nonintravenously administered prophylactic drug. Thus, I think fitusiran could have significant uptake/utilization in patients with hemophilia B with and without inhibitors.
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