Evaluating siRNA Therapy Fitusiran in Combination With Antithrombin Modulation for Hemophilia
Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, discussed findings from the open-label extension of the ATLAS studies at ASH 2024.
Steven W. Pipe, MD
At at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, presented data from the ATLAS-OLE clinical trial (NCT03754790) assessing fitusiran, an siRNA therapeutic targeting antithrombin, as prophylaxis in combination with appropriate bleed management guidelines for management of breakthrough bleeding in people with hemophilia A and hemophilia B. CGTLive®'s sister site HCPLive® sat down with Pipe at the conference to learn more.
Pipe explained the relevant background information behind the study and went over the key results. He concluded that fitusiran is a highly effective prophylactic agent and provides a better patient experience.
HCPLive: Can you discuss the ATLAS-OLE study and antithrombin guided dosing?
Steven W. Pipe, MD: It was my opportunity at this year's ASH meeting to present the experience with managing breakthrough bleeds in patients enrolled in the clinical trial program for fitusiran, a small interfering RNA molecule, which can be used to provide prophylaxis in patients with hemophilia A or B, with or without inhibitors, by knocking down antithrombin levels. As it does that, it helps restore the thrombin burst, or thrombin generation, as we call it. But it's also true that if you are adding a procoagulant on top of the antithrombin knockdown that this would further modulate thrombin generation. Early on in the clinical trial program for fitusiran, there was a voluntary hold because of thrombotic complications. One of the concerns was that the combination of procoagulants used to treat breakthrough bleeding with antithrombin knockdown could generate excessive thrombin burst, and might be at a root cause related to the thrombotic risk.
So what we came up with during the clinical trial program were what we call bleed management guidelines. In these guidelines, it recommended substantially reduced doses of factor VIII (FVIII), factor IX (FIX), or the bypassing agents, activated prothrombin complex concentrates (APCCs) and recombinant factor VIIa. Then, in addition to reduced doses, it was also recommended to have much more protracted intervals.
So the idea was actually conceived early on that because of the modulation of the thrombin burst already by fitusiran, that patients might be able to get better control of bleeds with substantially lower doses of both factor products and the bypassing agents. That's what this analysis was going to demonstrate.
There was one more risk mitigation that was put in place in the course of the clinical trial program. The original dosing regimen for fitusiran and was a fixed dose of roughly 80 mg once per month as a subcutaneous injection for prophylaxis. We had a substantial number of patients who were on that original dosing regimen. After additional look back at thrombotic events that had happened over the course of the clinical trial, we came back with a revised strategy for the dosing of fitusiran, in which we actually targeted the antithrombin levels to between 15% and 35% of normal. Now the reason that was chosen is that when we looked at the risk of thrombotic events in the clinical trial program, it seemed that there was an increased risk based on the percentage of time that patients spent with levels of antithrombin that were less than 10%. By targeting the lower bound at 15% we could avoid prolonged periods of time at less than 10% and then the upper bound of 35% was informed by what we knew from the efficacy data with fitusiran.
So the overall bleed management guidelines for managing breakthrough bleeding and then this new antithrombin dosing regimen were intended to enhance or optimize the benefit-risk profile of fitusiran prophylaxis.
So we now have taken the cohort of patients from what are called the ATLAS programs and they're in what's called an open-label extension (OLE) study, and they were shifted from the original dosing regimen (80 mg monthly), to this new antithrombin guided dosing regimen. We actually have just over 200 patients who were available for study under this new antithrombin dosing regimen. In addition, we have a subgroup of patients who we can use as a control group who had previously been on prophylaxis with either FVIII or FIX or bypassing agents. So we know what their bleed rates were while they were on prophylaxis with those agents. We also know what their factor consumption was when they were treating breakthrough bleeds while on those prophylactic regimens.
Now there's about 69 patients with hemophilia A or B with and without inhibitors that have now been followed in the OLE of the ATLAS program on the antithrombin dosing regimen. What I presented at this meeting is the efficacy on that regimen for preventing bleeds, and then what the factor consumption was when they had breakthrough bleeding while on the antithrombin dosing regimen with fitusiran. That's the whole setup here.
So what the data shows is fitusiran was highly effective as a prophylactic agent. It was substantially better than bypassing agent prophylaxis, with a 70% reduction in breakthrough treated bleeds on the antithrombin dosing regimen compared to bypassing agent prophylaxis. It showed comparable protection from bleeding to standard of care FVIII or FIX prophylaxis. That was the overall efficacy.
So what about when patients did have breakthrough bleeds? Well, the vast majority of individuals were able to control their bleeds by following the bleed management guidelines with these substantially reduced doses. What we also saw from the trial is not only did they get effective bleed control at the lower doses, they generally were able to get bleed control with just a single dose, as opposed to 2 or more doses of either factor products or the bypassing agents. If we look at the overall consumption as we call it, whether it's a mean annualized consumption of factor or if we look per bleed, there was between a 64% and almost 98% reduction in the amount of factor that was needed to treat breakthrough bleeding. This was across hemophilia A and B with or without inhibitors. I think the conclusion I take from this is that fitusiran is a highly effective prophylactic agent and the modulation of thrombin generation allows for achieving effective bleed control with substantially lower doses of factor and bypassing agents, as well as fewer infusions. This is just an overall better patient experience because if you're on an effective prophylactic agent, you're probably not infusing regularly anymore. The fact that you could look forward to, if you did have a breakthrough bleed, an effective bleed control in most patients, with just a single infusion at a much reduced dose, I think is a really great outcome for this trial.
This transcript has been edited for clarity.
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