WFH statement - EN

Joint Statement: Need for Adeno-Associated Virus (AAV) Antibody Screening in Persons with Hemophilia Considering Gene Therapy

With marketing authorization of the first gene therapy products for hemophilia A and B underway in Europe and the United States, the WFH, EHC and NHF have released a statement on the need for adeno-associated virus (AAV) antibody screening to help inform discussions between individuals with hemophilia and their physicians on the benefits and risks.

Also available in: Français Español

The following joint statement is issued by the World Federation of Hemophilia (WFH), the European Haemophilia Consortium (EHC), and the National Hemophilia Foundation (NHF).

With the marketing authorization of the first AAV vector-based gene therapy products for hemophilia A and B, patients, their caregivers, and healthcare professionals have many considerations in assessing the benefits and risks in the context of shared decision-making frameworks.1,2,3,4 One of the most important elements in the decision-making process is a person’s AAV antibody status. While both valoctocogene roxaparvovec (Roctavian, AAV5-Factor VIII) and etranacogene dezaparvovec (Hemgenix, AAV5-Factor IX) use the AAV5 vector capsid for transgene delivery and integration, 5,6 a notable difference between their implementation in clinical practice is the availability of a companion diagnostic (CDx) AAV5 antibody assay for the former to help inform benefit-risk discussions with patients.

AAV antibodies naturally occur in many individuals due to prior exposure to one or more AAVs present in nature. While AAV does not cause any known disease in humans, an antibody immune response develops upon exposure to the AAV virus. While the gene therapy AAV vector does not contain any of the viral genes present in natural AAVs, the capsid coating of the vector is unchanged, and individuals may have antibodies that can neutralize and prevent the AAV gene therapy from working. Thus, screening for antibodies to AAV was conducted for many AAV-based gene therapy clinical trials, and participants with AAV antibodies have been excluded from most AAV therapeutic programs.

For patients considering valoctocogene roxaparvovec, an AAV5 total antibody CDx assay has been CE marked and approved for use with valoctocogene roxaparvovec in Europe. This is required as part of the European Medicines Agency (EMA) license before treatment.7 A premarket approval application (PMA) has been filed for the same assay with the U.S. Food and Drug Administration (FDA). The WFH, EHC, and NHF urge the respective health authorities to ensure a similar level of assessment for valoctocogene roxaparvovec as this product completes its review and approval assessment in the United States.

In the etranacogene dezaparvovec clinical trials, patients were enrolled with or without neutralizing antibodies to AAV5. The study results showed that patients with a positive anti-AAV5 antibody titer (<1:678) responded well to the gene therapy, with mean factor IX activity levels in the same range but numerically lower compared to those without neutralizing anti-AAV5 antibodies.8 One patient with a high titer to AAV5 (1:3212) had no response. Based upon the Phase 3 study, the FDA and EMA have requested further evaluation of neutralizing antibodies in hemophilia B patients, particularly high-titer patients. In the meantime, data from the Phase 3 study suggest titers above 1:700 should be the upper limit for hemophilia B patients wishing to take etranacogene dezaparvovec therapy until further data become available to indicate the efficacy in patients with titers above this threshold. For etranacogene dezaparvovec, we support the utilization of the available assay used in clinical trials, to facilitate an informed discussion between patients and physicians regarding the benefits and risks of treatment until such time as a validated assay is available.

The WFH, EHC, and NHF believe that assessment of a hemophilia patient’s antibody titer to AAV5 should be required before initiation of treatment. Efforts should aim to minimize the risk of non-response or suboptimal therapeutic response, or compromising a patient’s future opportunities for an AAV-based gene therapy. Based on geography, the regulatory requirements and expectations differ concerning how these assays may be available to patients.

Going forward, we request that all gene therapy developers and regulators ensure an appropriate assay to assess antibody titers for AAV-based gene therapies is available contemporaneous with market authorization.

To read the joint statement, as a PDF please click here.


1 First gene therapy to treat severe haemophilia A. European Medicines Agency. News release, June 24, 2022. www.ema.europa.eu/en/news/first-gene-therapy-treat-severe-haemophilia

2 First gene therapy to treat severe haemophilia B. European Medicines Agency. News release, December 16, 2022. www.ema.europa.eu/en/news/first-gene-therapy-treat-haemophilia-b 

3 FDA Approves First Gene Therapy to Treat Adults with Hemophilia B. U.S. Food and Drug Administration. News release, November 22, 2022. www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b

4 Wang M, Negrier C, Driessler F, Goodman C, Skinner MW. The Hemophilia Gene Therapy Patient Journey: Questions and Answers for Shared Decision-Making. Patient Preference and Adherence. 2022;16:1439-1447. https://doi.org/10.2147/PPA.S355627

5 Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. New England Journal of Medicine. 2023;388(8):694-705. https://doi.org/10.1056/NEJMoa2211075

6 Pipe SW, Leebeek FWG, Recht M, et al. Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B. New England Journal of Medicine. 2023;388(8):706-718. https://doi.org/10.1056/NEJMoa2211644

7European Medicines Agency. Roctavian European public assessment report. Accessed March 7, 2023. www.ema.europa.eu/en/medicines/human/EPAR/roctavian-0

8 European Medicines Agency. Hemgenix European public assessment report. Accessed March 7, 2023. www.ema.europa.eu/en/medicines/human/EPAR/hemgenix

We’ve accomplished a lot this year, we need your help to continue strong.

Would you like to read more about similar articles?

Disclaimer

The information on the WFH website is provided for general information purposes only. The WFH does not engage in the practice of medicine and under no circumstances recommends particular treatment for specific individuals. For diagnosis or consultation on a specific medical problem, the WFH recommends that you contact your physician or local treatment centre. Before administering any products, the WFH urges patients to check dosages with a physician or hemophilia centre staff, and to consult the pharmaceutical company’s printed instructions.

While every effort has been made to ensure the accuracy of the information on this site, the WFH does not guarantee the information is accurate, and is not responsible in any way whatsoever for damages arising out of the use of this website or any of the information contained herein.

Messages posted to WFH discussion forums, Facebook, Twitter, and other social media platforms do not represent the opinions of the World Federation of Hemophilia, its staff, or Board of Directors. The author of a message is solely responsibility for its content. Information posted on WFH social networks and platforms should never be a substitute for individualized professional medical advice, even when the author has medical qualifications or is considered an authority. Information posted to a discussion group should not be used to diagnose or treat a specific health problem without consulting a qualified healthcare professional. The WFH recommends that you contact your physician or local treatment centre if you have any individual questions or concerns.

References and links to other websites or references to other organizations, products, services, or publications do not constitute endorsement or approval by the WFH. The WFH is not responsible and assumes no liability for the content of any linked websites.

Fraud Alert

Unauthorized solicitations – Warning

The WFH has been made aware of various correspondences—circulated via e-mail and telephone—coming from individuals impersonating WFH staff or falsely stating that they are associated with the WFH. These correspondences, which may seek to obtain money using the name of someone affiliated with the WFH, are fraudulent and come from outside of our organization.

If you receive a suspicious solicitation, exercise extreme caution. In the case of an email, look at the email address to see if it looks suspicious (for example, all WFH emails come from @wfh.org).

We are asking you to remain vigilant, and if you have any doubts about the correspondence, please forward the email to the WFH at [email protected] or call +1 514-875-7944.