Skip to Main Content

Advertisement intended for health care professionals

Skip Nav Destination

Fitusiran: Taking a (re)Balanced Approach to Hemophilia Therapy

December 13, 2021
Patrick Ellsworth, MD

Dr. Patrick Ellsworth (@PEllsworthMD) is an Assistant Professor of Medicine in the Division of Hematology at the University of North Carolina at Chapel Hill. He specializes in adult and pediatric hematology with interests in nonmalignant hematology, especially sickle cell disease and bleeding disorders. His research interest lies in the interaction of endothelium with blood cells via coagulation proteins. Dr. Ellsworth hails from lovely Salmon, Idaho, and currently calls Cary, North Carolina, part of the famous Research Triangle, his home. Outside of his rigorous efforts to treat patients with nonmalignant blood diseases, Dr. Ellsworth enjoys hanging out with his wife and four children. 

Congenital hemophilia A (HA) and B (HB) are inherited bleeding disorders for which inhibitor development remains a significant complication, resulting in bleeding despite factor therapy. Inhibitors are more common in severe HA than in non-severe HA, with an incidence of 25 to 30 percent. In HB, inhibitor incidence is 3 to 5 percent . Even with attempted immune tolerance induction and immunosuppression, inhibitors recur in up to 30 percent of HA and 20 percent of HB patients. 

Treatment of HA has dramatically changed just since the first year of my hematology fellowship (back in 2016). The introduction of emicizumab for patients with HA has been transformative for the field and for patients. But this paradigm shift in HA has left patients with HB wanting, if not outright jealous. Non-factor therapy in HB is trickier. Factor VIIIa acts as a cofactor rather than a serine protease like factor IXa; therefore, it was inherently and theoretically more straightforward to “replace” a cofactor whose job it is to essentially bring two other factors close together without any proteolytic activity itself. 

Efficacy in gene therapy chartFitusiran aims to rebalance the hemostatic system with roots in observational science from the 90s and early 2000s. With the advent of genome sequencing came the ability to evaluate large numbers of patients with inherited bleeding disorders but milder phenotypes than expected. Factor V Leiden and prothrombin 20210G>A mutations (among others) were found to mitigate bleeding risk in patients with HA and HB. By the late 2010s, it was well-established in animal models of hemophilia that decreased expression of antithrombin prevented bleeding. Fitusiran is a small-molecule RNA interference therapeutic that acts by binding and degrading mRNA-encoding antithrombin, partially silencing the expression of the antithrombin gene. With a hemostatic challenge, this results in increased total thrombin generation as compared to someone who isn’t having their antithrombin therapeutically decreased. 

In early phase clinical trials, doses of fitusiran were given with a target antithrombin activity of 20 percent. This normalized thrombin generation and reduced bleeding, but trials were briefly paused when a patient died after developing a dural sinus thrombosis following high-dose factor VIII administration some months after cessation of fitusiran. Revised dosing and antithrombin targets were adopted for ongoing portions of the phase III study. At Sunday’s Plenary Scientific Session, Dr. Guy Young (pictured) presented the phase III results from the higher subcutaneous, monthly dose of 80 mg – results that many in the hemostasis community have been eager to see. 

This study enrolled 57 participants (45 with HA, 12 with HB), 38 of whom were in the fitusiran arm. Twenty-seven of the subjects receiving fitusiran experienced no bleeding complications (65.8%, but a median annualized bleeding rate [ABR] of 0). Seven patients in the treatment arm had at least one adverse event (including 4 thrombotic events, one requiring withdrawal from the study). Regarding the thrombotic events, Dr. Young clarified that those events were seen in patients observed to have antithrombin levels at the lower end of ranges seen in the study (some as low as 10-20%).  

I can’t help but compare this to emicizumab, which in recent long-term follow up of the HAVEN 1-4 trials showed 82.4 percent of patients having no treated bleeds and seven thrombotic events in 399 total patients. I readily admit this is an apples-to-oranges comparison; lest I be accused of being hard-to-please, it needs to be said that a 5 percent thrombosis rate does compare favorably to bypassing agents. Although that is an admittedly low bar (there I go with the hard-to-please stuff again), bypassing agents are what patients with HB with inhibitors have been stuck with until now. 

The study included metrics evaluating patient quality of life, with significant improvements in the treatment arm compared to on-demand bypassing agents. These metrics are thankfully finding their way into more clinical trials in nonmalignant hematology and should be here to stay. Numbers of bleeds aside, the quality-of-life improvements are substantial, and Dr. Young memorably highlighted the hardships faced by parents, children, and adults dealing with IV infusions of factor. 

In light of the early-phase adverse event noted above, I am not surprised at the thrombotic events, and although the median ABRs look fantastic, seeing that one in three of the patients still had some bleeding leaves me feeling somewhat disappointed overall. However, advancing these rebalancing therapies is going to be an iterative process, and this is the first step in a small group of very high-need patients. The underwhelming results in bleed rates notwithstanding, these data for fitusiran are absolutely a win for patients with HB with inhibitors. This drug is poised to make the greatest impact for this group of patients who badly need effective therapy. Another consideration is that this is a medication given monthly subcutaneously. The convenience of this kind of dosing can’t be understated for our patients, many of whom have resigned themselves to the unpleasant routine of intravenous access many times a week. But for HA, does fitusiran offer an advantage versus emicizumab? Based on these data, I don’t see a compelling reason to favor fitusiran over emicizumab to treat someone with HA. But for our HB patients with inhibitors, fitusiran is clearly poised to drastically reduce their treatment burden.  

Now that we have something to offer HB patients with inhibitors, does fitusiran mark the end of factor therapy? Is such a thing desirable? I co-wrote the manuscript in Hematology that accompanies the session “Hemophilia Update: Our Cup Runneth Over - Live Q&A” and which addresses this topic. There are cases in which factor is still necessary and preferred. Also, I find clinically that some patients are very attached to their factor, much like I still like to take notes on paper. In the end, options are always a good thing, and it’s why we pursue the science in the first place. As a fellow and now practicing physician and scientist, it has been exciting to see the bench make it to the bedside, even if the road has been, and continues to be, a little bumpy. 

Dr. Ellsworth indicated no relevant conflicts of interest. 

Close Modal

or Create an Account

Close Modal
Close Modal