The paper introduced here is the following.
Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial
Efficacy and safety of fitusiran prophylaxis in patients with haemophilia A or haemophilia B who have inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial
A brief explanation…
Hemophilia is an inherited disorder, transmitted mainly on the X chromosome, in which a deficiency of blood coagulation factors makes a person prone to bleeding. Hemophilia A and hemophilia B are the common forms, caused by a shortage of blood coagulation factor VIII or IX, respectively.
A therapeutic drug administered to supplement a blood coagulation factor can sometimes be recognized as a foreign substance within the patient’s body. As a result, the immune system produces antibodies (inhibitors) that attack the therapeutic drug, reducing its effectiveness. Although the cause of inhibitor formation is not fully understood, genetic and environmental factors, as well as the timing and frequency of treatment, are thought to be involved.
Fitusiran is a new drug used to treat hemophilia A and B, and it employs a technology called RNA interference (RNAi). In RNA interference, a small double-stranded RNA molecule (siRNA) specifically binds to a target messenger RNA (mRNA), thereby preventing the mRNA from being translated. This suppresses the production of the protein encoded by the target gene.
Fitusiran aims to enhance the patient’s blood coagulation ability and reduce the risk of bleeding by suppressing the production of antithrombin, an anticoagulant protein. Unlike conventional hemophilia treatments, fitusiran does not act directly on blood coagulation factors, so it is considered less susceptible to the effects of inhibitors.
This article reports the results of a phase 3 trial that evaluated the efficacy and safety of fitusiran prophylaxis in patients with hemophilia A or B who have inhibitors. In this study, fitusiran prophylaxis was found to be effective at reducing the bleeding rate and to be well tolerated.
The background of this study
It is explained that the process of stopping bleeding, called hemostasis, requires a balance between procoagulant and anticoagulant pathways. Hemophilia A and B are caused by a deficiency of coagulation factors, which can result in insufficient thrombin generation and bleeding. The standard treatment in hemophilia management is prophylaxis—that is, the regular administration of hemostatic agents—but it has limitations such as the need for frequent infusions and the development of inhibitory antibodies.
How was the experiment conducted?
In this paper, a multicentre, randomised, open-label phase 3 trial was conducted to evaluate the efficacy and safety of fitusiran prophylaxis in patients with hemophilia A or B who have inhibitors. Participants were randomly assigned either to a group receiving 80 mg of subcutaneous fitusiran prophylaxis once a month, or to a group continuing on-demand bypassing agent therapy for 9 months. The primary endpoint was the mean annualized bleeding rate during the efficacy period in the intention-to-treat population, estimated by a negative binomial model. Safety was evaluated as a secondary endpoint in the safety population.
Bypassing agent therapy is a treatment method used when inhibitors are present in hemophilia patients. In ordinary hemophilia treatment, the missing blood coagulation factor is replaced to restore clotting function, but when inhibitors are present, the effect is reduced. In bypassing therapy, instead of the missing coagulation factor, another substance (a bypassing agent) that promotes the coagulation cascade is used. This makes it possible to improve the blood’s clotting ability and control bleeding while avoiding the effects of inhibitors. Representative bypassing agents include activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa).
What results were obtained?
In this study, fitusiran prophylaxis was found to be associated with a substantial reduction in the bleeding rate compared with on-demand bypassing agents. The median annualized bleeding rate was 0.0 in the fitusiran prophylaxis group and 16.8 in the on-demand bypassing agent group. The safety profile of fitusiran was consistent with previous studies, and no new safety concerns were identified. All participants completed the study.
A value of 1 or below means that the fitusiran group had the better outcome.
What are the limitations of this study?
It evaluated the efficacy and safety of fitusiran prophylaxis only in patients with hemophilia A or B who have inhibitors, and did not evaluate it in patients without inhibitors. In addition, because this study was open-label, the results may have been subject to bias. Finally, because this study was conducted over a relatively short period of 9 months, the long-term safety and efficacy of fitusiran prophylaxis remain unknown.
What is next for this study?
This paper notes that, because actual variability in test values between local assays was observed in this study (since different facilities use different testing instruments, the test data can vary even for the same coagulation state), future studies will need to investigate the acceptable measurement limits for the antithrombin local assay.
The possibility of individualizing and optimizing fitusiran therapy based on individual responses is also under investigation.
Impressions
This is a paper I became interested in because I have also dabbled in research on the coagulation system. The bleeding problems of hemophilia can be serious; in particular, when bleeding occurs within a joint, the activities of daily living (ADL) decline dramatically. Treatments using RNAi are gradually beginning to be applied clinically, and they deserve attention. Since such solid data could be produced in Phase 3, the researchers in charge of this study must have been relieved. I would like to be able to produce results like this in my own research too.