Ongoing Trial Investigates Switching from Emicizumab to Fitusiran in Hemophilia A, With Guy Young, MD

SWITCH, an ongoing exploratory, open-label, single-arm Phase 1 study, is actively investigating the process of transitioning from emicizumab to fitusiran for the treatment of severe hemophilia A.1

Hemophilia A results from a mutation in the genes that encode clotting factor VIII, which leads to a disruption in the contact activation pathway of coagulation. Most patients are male, due to the condition’s X-linked recessive inheritance pattern. Patients with severe hemophilia A require consistent, regular replacement therapy with FVIII to maintain factor levels at 1-3% of the normal value, to prevent bleeding diathesis and its complications.2

Current therapies are produced either from human plasma or recombinant DNA technology using human and nonhuman cells. Protein modification techniques have also been employed to extend the plasma half-life of recombinant clotting factors, which reduces the number and frequency of injections. However, patients often develop neutralizing antibodies against FVIII, the incidence of which is roughly 20-30% in patients with severe hemophilia A.2

“Unlike medications like Factor, which have a short half-life, switching from emicizumab to another drug is tricky because it has a longer half-life,” Guy Young, MD, director of the Hemostasis and Thrombosis program at Children’s Hospital Los Angeles and professor of pediatrics at Keck School of Medicine of USC, told HCPLive in an exclusive interview. “It takes weeks to months before emicizumab washes fully out of your system. We don’t want the full amount of emicizumab in the blood when we start fitusiran, because it could increase the risk of thrombotic events, so it could compromise patient safety.”

SWITCH consists of a 60-day screening period, a 2-month pre-fitusiran treatment period to allow the washout of emicizumab, and an 18-month fitusiran prophylaxis period. The washout strategy was determined via a combination of modeling and simulation data to predict factor VIII-like activity equivalence. A population-pharmacokinetic model was utilized to draw a direct link between emicizumab exposure during the washout period and factor VIII-like activity.1

Young and colleagues conducted simulations of antithrombin levels in participants receiving fitusiran, inputting this data into a quantitative systems pharmacology model to predict factor VIII-like activity in people with severe hemophilia A. Through this, the total FVIII-like activity from both emicizumab and fitusiran was assumed to be additive, implying a total factor VIII-like activity of <50% with fitusiran administration around 2 months after the last emicizumab dose.1

During the trial, participants will start fitusiran treatment once every 2 months (Q2M), although investigators may escalate or de-escalate the dose to target antithrombin activity levels of 15-35% and maintain sufficient bleed protection. The first 3 sentinel participants are treated in a stepwise fashion, which requires 1 patient to complete 1 month of fitusiran treatment before the next participant may begin.1

After the final dose, antithrombin activity will be monitored monthly during the 6-month antithrombin follow-up period. Investigators have established a primary endpoint of incidence, severity, and seriousness of adverse events from day 1 to month 4 of fitusiran treatment. Secondary endpoints include lab assessments of peak thrombin generation and antithrombin levels from day 1 to month 4, emicizumab plasma concentrations up to the end of washout, and incidence, severity, and seriousness of adverse events from day 1 to month 18 of fitusiran treatment. Young and colleagues also plan to monitor health-related quality of life measures from baseline to the end of the study period, change in participant joint health, and annualized bleeding rate for the 14-month extension.1

A total of 15-20 male patients aged ≥18 years have been enrolled in the study so far, all with severe hemophilia A and both with and without inhibitors. However, enrollment is still ongoing.1

“If you want to be completely safe from a thrombotic standpoint, you can stop emicizumab, wait 6 months for it to be fully washed out, and then you could start the fitusiran,” Young said. “But the problem with that is that it’ll leave the patient unprotected from bleeding for at least a 2, 3, maybe even 4-month period, and that’s the last thing we want to do. The question that the SWITCH study is aiming to answer is when is the right time to stop emicizumab and start fitusiran, to thread that needle?”

Editor’s Note: Young reports disclosures with BioMarin, Genentech/Roche, Pfizer, CSL Behring, ASC Biotherapeutics, Alnylam, and others.

References

1. Young G, Kaddi C, Ali S, et al. Evaluating the safety and tolerability of switching from emicizumab to fitusiran prophylaxis in adult males with severe hemophilia A, with or without inhibitors: Switch Study, a trial in progress. Blood. 2025;146(Supplement 1):3076-3076. doi:10.1182/blood-2025-3076

2. Wichaiyo S. Advances in Development of Drug Treatment for Hemophilia with Inhibitors. ACS Pharmacol Transl Sci. 2024;7(12):3795-3803. Published 2024 Nov 8. doi:10.1021/acsptsci.4c00560