After several decades of preclinical and clinical research, pitfalls and progress, gene therapies for hemophilia A and B have become a reality with recent FDA approvals. While these therapies, along with others still in development, represent both promise and a notable scientific achievement, outstanding questions relevant to long terms efficacy and safety remain. Authors of a new review “Hemophilia Gene Therapy: First, Do No Harm,” published in the Journal of Thrombosis and Haemostasis (JTH), tackle these concerns.

The authors address fundamental considerations for people with hemophilia (PwH) patients, cognizant that each individual has their own personal health goals, lived experiences, and comfort level with open-ended questions of long-term risk vs. therapeutic benefits. Safety, in context of the hemophilia communities’ unique history, is a prominent through line in this paper. They cite multiple concerns, including the potential for both innate and adaptive immune responses to adeno-associated viral (AAV) vectors and to the possible integration of the given vector into the genome of gene therapy recipients. These types of responses could have safety and efficacy impacts, including inflammatory effects on the liver or the development of tumors or malignancies.  

“Gene therapy is a complex biological 'drug' for which, despite 30 years of development, there are many unresolved questions, and the unknowns remain top of mind for clinicians and PwH alike. Evaluation of the risks and benefits of any new therapy requires the careful consideration of all the available information and a shared decision-making approach should be employed, explain the authors. “This is particularly important in the consideration of gene therapy, given the fact that AAV-mediated gene therapy is a one-time irreversible therapy. A fully informed decision must be ensured, and a robust shared decision-making approach is mandatory for these therapies.”

The review summarizes clinical trial data that supported the regulatory authorization of valoctocogene roxaparvovec in Europe to treat hemophilia A and etranacogene dezaparvovec-drlb in Europe and the United States to treat hemophilia B. NOTE that since the publication of this paper, valoctocogene roxaparvovec  also received U.S. Food and Drug Administration approval under the brand name ROCTAVIAN™.

The authors highlight initiatives taken by NHF and other organizations to prioritize safety for hemophilia patients who are either considering gene therapy or for those who have received the one-time treatment. A primary example of this is NHF’s submission of a Citizen Petition to the FDA in 2022 requesting that a Risk Evaluation and Mitigation Strategy (REM) be required as a condition of approval for both valoctocogene roxaparvovec and etranacogene dezaparvovec. Read the full petition to learn more.

While the aforementioned products received FDA approval without meeting the REM requirements, the document’s key elements remain germane to protecting long term patient safety. These include training and education for healthcare providers (HCPs) on gene therapy and its management in patients with hemophilia, with particular emphasis on the central role of shared decision making (SDM). The crucial function of facilities charged with administering gene therapies, specifically federally funded hemophilia treatment centers, is also emphasized.

The authors stress the importance of high enrollment in the World Federation of Hemophilia’s global gene therapy registry, ideally placed to collect adverse event data and other developments from patients who receive these products. Steps towards achieving greater health equity, including broader representation in clinical trial design, is also a focus.

The paper concludes with a series of recommended steps that could be taken within the hemophilia community to ensure the safety and optimal outcomes for PwH who might opt to receive a gene therapy product. These recommendations dovetail closely with the elements of the earlier REM. This article is currently available in PDF on the JTH website.

NHF also recorded a webinar that serves as an excellent companion resource to the review article. It was presented by lead author Leonard A. Valentino, MD, President, and CEO of NHF.

Lastly, please see this additional paper highlighting a great tool for SDM and gene therapy.

Valentino LA, Kaczmarek R, Pierce GF, Noone D, O'Mahony B, Page D, Rotellini D, Skinner MW, Hemophilia Gene Therapy: First, Do No Harm Journal of Thrombosis and Haemostasis (2023), doi:

Disclaimer: NHF provides periodic synopses of articles published in peer reviewed journals, the purpose of which is to highlight papers that cover a wide range of topics and speak to a broad spectrum of the inherited blood disorders community. Topics include shared decision making, gene therapy, health equity, and more. NHF hopes you find this content to be informative and engaging.

Any questions about the articles featured here should be directed to the publishing journal and/or the study authors. This content is for general information only. NHF does not give medical advice or engage in the practice of medicine. NHF under no circumstances recommends particular treatment for specific individuals and in all cases recommends that you consult your physician or HTC before pursuing any course of treatment.