Guy Young, MD, is the director of the Hemostasis and Thrombosis program at Children’s Hospital Los Angeles and professor of pediatrics at Keck School of Medicine of USC.

Guy Young, MD

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 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.

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.

“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 

 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.

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.

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.

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.

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.

“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.

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. 

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. 

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The SWITCH phase 1 trial aims to determine the optimal time to switch medications to minimize thrombotic risk and avoid leaving patients untreated.

Young shared with his real-world experiences with etranacogene dezaparvovec gene therapy.

A Positive Outlook on Gene Therapy for Hemophilia B Post-Discontinuation, with Guy Young, MD

Pfizer recently announced that it was discontinuing development and commercialization of fidanacogene elaparvovec an adeno-associated virus (AAV) vector-based gene therapy for the treatment of hemophilia B.

The therapy was approved only 1 year ago, in April 2024, under the name Beqvez.

Upon approval, fidanacogene elaparvovec joined pioneer gene therapy etranacogene dezaparvovec-drlb, approved by the FDA under the name Hemgenix for the same indication in 2022.

HCPLive spoke with Guy Young, MD, Director, Hemostasis and Thrombosis Program, Children’s Hospital of Los Angeles, and Professor of Pediatrics, Keck School of Medicine of University of Southern California, who served as an investigator on the etranacogene dezaparvovec program and who has administered it in the commercial setting, to learn more about his outlook on gene therapy in the hemophilia B field amidst the discontinuation.

Young stressed that his outlook on gene therapy in the field remained positive. He shared his experiences with etranacogene dezaparvovec in the real world and the patient and clinician reception.

“I think that the field is ready. We're seeing more and more patients receiving this,” Young said. “I think with gene therapy, there was all this excitement, and then it… kind of died off. But I think we're at that point where, where the tide is going to turn… the future products will be either different or better, or offer things that Hemgenix cannot offer… I think that hemophilia patients are excited about and are ready for products that can provide them the potential for getting cured.”

Young’s relevant disclosures included Genentech/Roche, Grifols, and Takeda, BioMarin, Novo Nordisk, Sanofi, Spark, Takeda, and UniQure.

Santhosh C. Pfizer stops commercialization of hemophilia gene therapy Beqvez. Reuters. February 21, 2025. Accessed April 25, 2025. 

https://www.reuters.com/business/healthcare-pharmaceuticals/pfizer-says-it-will-end-global-development-gene-therapy-beqvez-nikkei-reports-2025-02-20/

U.S. FDA Approves Pfizer’s BEQVEZ™ (fidanacogene elaparvovec-dzkt), a One-Time Gene Therapy for Adults with Hemophilia B. News release. Pfizer. April 26, 2024. Accessed April 25, 2025. https://www.businesswire.com/news/home/20240425269649/en/U.S.-FDA-Approves-Pfizer%E2%80%99s-BEQVEZ%E2%84%A2-fidanacogene-elaparvovec-dzkt-a-One-Time-Gene-Therapy-for-Adults-with-Hemophilia-B

Johnson V. FDA approves first gene therapy for hemophilia B. HCP Live. November 23, 2022. Accessed April 25, 2025. https://www.hcplive.com/view/fda-approves-first-gene-therapy-hemophilia-b.

Guy Young, MD

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