Professor and Laurence A. Boxer Research Professor of Pediatrics and Professor of Pathology, University of Michigan and CS Mott Children’s Hospital, Ann Arbor, Michigan

Steven W. Pipe, MD

HOPE-B: 5-Year Etranacogene Dezaparvovec Maintains Durable Efficacy and Safety in Hemophilia B, With Steven Pipe, MD

Analysis from the HOPE-B trial shows that a single dose of etranacogene dezaparvovec maintains durable, endogenous factor IX (FIX) Padua expression and produces sustained reductions in bleeding rates among adults with severe or moderately severe 

67th American Society of Hematology (ASH) Annual Meeting and Exposition

 by Steven Pipe, MD, a professor of pediatrics and pathology at the University of Michigan, and provide the longest follow-up data to date from a phase 3 trial of gene therapy in hemophilia B, evaluating long-term durability of FIX expression, efficacy, and safety.

“For patients who want to be freed from regular regular factor IX infusions, this is really the only therapeutic strategy that can offer that,” Pipe explained in an interview with 

. “A single infusion giving years of stable expression and bleed protection is truly transformative. The earlier patients receive that benefit, the more we can change their long-term joint health trajectory.”

Etranacogene dezaparvovec (Hemegenix) is an adeno-associated virus vector-based one-time gene therapy. In 2022, the 

 approved etranacogene dezaparvovec as the first gene therapy for adults with hemophilia B who use factor IX prophylaxis therapy and have current or prior life-threatening bleeding or repeated spontaneous bleeding episodes.

“Integrating gene therapy into routine clinical practice requires substantial planning, building infrastructure, training staff, and refining workflows, it’s very different from administering factor replacement,” said Pipe. “But with the right systems in place, we can make the experience manageable for patients by leveraging local labs and minimizing disruptions to their daily lives.”

These findings were demonstrated by HOPE-B, a phase 3, open-label, single-arm clinical trial where patients received a single intravenous infusion of etranacogene dezaparvovec (2×10¹³ gc/kg) after a ≥6-month lead-in period of standard-of-care FIX prophylaxis to establish baseline bleeding rates. Efficacy endpoints included annualized bleeding rates (ABR), endogenous FIX activity, and exogenous FIX usage. Safety assessments included adverse events, liver function, and long-term risks such as oncogenicity.

The study population was comprised of adult males with severe or moderately severe hemophilia B (FIX ≤2%) with or without preexisting AAV5 neutralizing antibodies. Of 54 participants treated with etranacogene dezaparvovec, 50 completed 5 years of follow-up.

Investigators observed a significant reduction in ABR for all bleeds, from 4.16 during the lead-in period to 1.52 during months 7–60 post-gene therapy (rate ratio 0.37; 95% Confidence Interval [CI], 0.18–0.76; 

 = .0035). Annualized bleed rates at years 1, 2, 3, 4, and 5 were 1.33 (n = 54), 0.91 (n = 54), 0.83 (n = 53), 0.40 (n = 51), and 0.40 (n = 51), respectively. Spontaneous ABR decreased from 1.52 during the lead-in to 0.53 during months 7–60 (

 = .0133). Joint ABR decreased from 2.34 to 0.35, and traumatic ABR decreased from 2.01 to 0.34 (

During years 1-5, mean endogenous FIX activity remained stable at >36%, with similar outcomes in NAb-positive and -negative participants. Exogenous FIX use decreased by 96%, from 257,339 IU/year during the lead-in period to 10,924 IU/year during months 7–60 post-gene therapy (

 <.0001). Only 1 participant resumed FIX prophylaxis at 30 months following a decrease in FIX activity to 2-5% and the occurrence of spontaneous bleeding events.

Over the 5-year follow-up, investigators reported a total of 100 treatment-related adverse events (AE) in 39 participants. Most occurred within the first 4 months post-gene therapy, with only 5 occurring between years 4 and 5. The most frequent AE was alanine aminotransferase elevation (n = 10). According to investigators, only 9 participants received corticosteroids for a mean of 81.4 days (range, 51–130 days). They observed no long-term hepatotoxicity or AAV-related oncogenicity.

Consenting HOPE-B participants will continue long-term monitoring up to 15 years in the IX-TEND 3003 study.

Editor’s Note: Pipe reports relevant disclosures with Bayer, BioMarin, Chugai, and others.

Pipe S, Miesbach W, Recht M, et al. End-of-study analysis of the HOPE-B trial confirms the durable efficacy and safety of etranacogene dezaparvovec hemophilia b gene therapy over 5 years. Abstract presented at the 67th American Society of Hematology Annual Meeting. Orlando, FL. December 6-9, 2025.

Heo YA. Etranacogene Dezaparvovec: First Approval. 

. Published online February 21, 2023. doi:

https://doi.org/10.1007/s40265-023-01845-0

Iapoce C. Hemophilia B Gene Therapy Achieves Sustained Benefit Over 4 Years. 

 February 7, 2025. Accessed December 10, 2025. https://www.hcplive.com/view/hemophilia-b-gene-therapy-achieves-sustained-benefit-over-4-years

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End-of-study analysis from the HOPE-B trial shows durable endogenous FIX expression, reduced annualized bleeding rates, and a favorable safety profile.


Fitusiran Achieves Sustained Antithrombin Activity Regardless of Dose with Steven Pipe, MD

A review of clinical and population data from the ATLAS-OLE trial has characterized the pharmacokinetics and pharmacodynamics of fitusiran in patients with 

, using dose guidance provided by a Population Pharmacokinetic-Pharmacodynamic (PopK-PD) model. Fitusiran achieved steady-state antithrombin activity (AT) within the 15-35% target range with 0 to 1 dose changes in most patients.

Fitusiran is a subcutaneous small interfering RNA therapeutic targeting antithrombin to rebalance homeostasis in patients with hemophilia A or B. It was officially approved by the 

ATLAS-OLE is an interventional phase 3 trial. Begun in January of 2019, ATLAS-OLE is still ongoing and is expected to end in November of 2026. Patients received fitusiran AT-DR 50 mg either monthly or every two months, and were adjusted to 20 mg if a change was needed based on AT levels. A total of 17,358 samples were collected from 339 participants for the clinical and population data review. Investigators conducted simulations on these samples using a PopK-PD model, which was developed using data pooled from prior phase 1/2/3 studies. The study aimed to maintain AT levels between 15 and 35%.

Ultimately, these simulations predicted that >99% of participants will reach steady-state AT within 19.9 to 22.7 weeks following initiation of fitusiran, regardless of dose regimen. These results are consistent with clinical observations. Additionally, following discontinuation of fitusiran, AT activity was projected to remain <60% for roughly 20 weeks. Covariates such as weight had no significant effect on the model parameters.

A collective 80 participants (37.6%) required no dose changes, 120 (56.3%) required 1 dose change, and 13 (6.1%) required >1 dose change to achieve AT activity 15-35%. Median time to reach final dose was 111 days (interquartile range, 0; 280).

Steven Pipe, MD, professor of pathology and Laurence A. Boxer Research Professor of Pediatrics at the University of Michigan, sat down with 

 to discuss the results of the review and the implications for hematology at large.

“What really impressed me as we went through this population PK and pharmacodynamic assessment is how many patients are going to be fine on the starting dose of 50 mg every other month and will not require any dose changes,” Pipe told 

. “And if you do a dose change, it’s most likely that you would actually do a dose change to a lower dose.”

Pipe also explained the impact these data may have on the future of hemophilia A and B treatment.

“This is really going to realize an effective prophylactic regimen for patients with just six subcutaneous doses a year,” Pipe said. “And then, on the edges, there may be patients that need a monthly regimen, or might need some additional monitoring.”

Pipe noted the convenience and easy transportability of the proposed pen delivery device, which, based on these findings, will be fixed at 50 mg per dose.

“The other thing about the delivery of this device that I think is going to be attractive to patients is that it comes in a prefilled syringe,” Pipe continued. “It’s basically a pen, if you like, and the 50 mg, which is going to be the predominant dose that people are on, will be the fixed syringe. And this has long stability at room temperature for several months. It’s going to make it easy for people to travel if they need to bring it with them.”

Editors’ Note: Pipe reports disclosures with Siemens, Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, Bayer, Biomarin, and others.

Kenet G, Nolan B, Zulfikar B, et al. Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial. Blood. 2024;143(22):2256-2269. 

Long-term Safety and Efficacy Study of Fitusiran in Patients With Hemophilia A or B, With or Without Inhibitory Antibodies to Factor VIII or IX (ATLAS-OLE). ClinicalTrials.gov identifier: NCT03754790. Updated July 15, 2024. Accessed July 23, 2025. 

https://clinicaltrials.gov/study/NCT03754790

Pharmacodynamics and pharmacokinetics of fitusiran antithrombin-based dose regimen (AT-DR): clinical and population modeling data. Presented at the 2025 International Society for Thrombosis and Heamostasis Congress in Washington, DC, June 21-25, 2025.

A review of data from an ongoing phase 3 trial indicates the potential for a generalized, prespecified fitusiran treatment for hemophilia A and B.

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Pipe discussed a symposium at ASH 2024 about practical implementation of gene therapy in the field.

Steven W. Pipe, MD: Supporting Gene Therapy Implementation for Hemophilia

As gene therapies grow in prominence in the hemophilia field, discussions are needed around the practical implementation of gene therapies, whether concerning the differences in gene therapies for hemophilia A and hemophilia B, accurately identifying eligible candidates for gene therapy, monitoring patients with hemophilia who receive gene therapies, and counseling patients and colleagues about gene therapies.

 66th American Society of Hematology (ASH) Annual Meeting and Exposition

, held December 7-10, 2024, in San Diego, California. Participants included Steven W. Pipe, MD, Professor and Laurence A. Boxer Research Professor of Pediatrics and Professor of Pathology, University of Michigan and CS Mott Children’s Hospital, Ann Arbor, Michigan; Doris V. Quon, MD, PhD, Associate Medical Director at Sarcoma Oncology Center; and Amy L. Dunn, MD, Director of Pediatric Hematology, Hemophilia Treatment Center, Nationwide Children's Hospital.

“I was surprised, even in my own clinical setting, that some of the institutional hurdles we had to go through are different than what we had to set up the clinical trial program. And so, I believe a lot of centers are now just sort of working through those processes,” Pipe told 

spoke with Pipe to learn more about the discussion and its main takeaways. He emphasized the importance of helping to guide patients and colleagues through determining eligibility for gene therapy and achieving clinical readiness for administering gene therapy. He noted that payers are beginning to understand the cost-effectiveness of gene therapy and thus, he thinks that education and hesitancy for clinicians and patients have overcome cost as the primary deterrent for gene therapy.

Pipe SW, Quon DV, Dunn A. Clinical assessment of gene therapies for hemophilia A and hemophilia B: Key takeaways for your practice. Presented at: ASH Annual meeting; December 7-10; San Diego, California. Satellite symposium.

Pipe discussed findings from the open-label extension of the ATLAS studies at ASH 2024.

Steven W. Pipe, MD: Fitusiran With Anti-Thrombin Modulation Yields Effective Bleed Control, Reduces Infusions

Fitusiran prophylaxis, in combination with appropriate bleed management guidelines, allowed fewer infusions and lower doses of clotting factor concentrates (CFC) or bypassing agents (BPAs) to treat breakthrough bleeding in people with hemophilia A or B.

These findings, from the ATLAS OLE study, were presented at the

, held December 7-10, 2024, in San Diego, California, by Steven W. Pipe, MD, Professor and Laurence A. Boxer Research Professor of Pediatrics and Professor of Pathology, University of Michigan and CS Mott Children’s Hospital, Ann Arbor, Michigan.

“Fitusiran is a highly effective prophylactic agent. The modulation of thrombin generation allows us to achieve effective bleed control with substantially lower doses of factor and bypassing agents, as well as fewer infusions. And this is just an overall better patient experience,” Pipe told 

Pipe and colleagues found that doses per bleed for participants without inhibitors and with inhibitors was reduced during fitusiran prophylaxis as compared to the CFC/BPA prophylaxis period, and overall, participants required fewer infusions for the management of breakthrough bleeds with fitusiran antithrombin-based dosing regimen (with inhibitors, 57; without inhibitors, 148) versus those who received CFC (n = 189) or BPA (n = 465) prophylaxis.

Pipe SW, Kavakli K, Matsushita T, et al. Reduced Doses of Factor Concentrates and Bypassing Agents to Treat Breakthrough Bleeds in Patients with Hemophilia A and B on Fitusiran Antithrombin-Based Dosing Regimen: ATLAS-OLE. Presented at: ASH Annual meeting; December 7-10; San Diego, California. Abstract 128.

Steven W. Pipe, MD

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