08 Dec Gene Therapy Liberates Hemophilia B Patients from Requiring Regular Infusions of Clotting Factor

MedicalResearch.com Interview with:

Dr. Pipe

Steven Pipe, MD
Professor of Pediatrics and Pathology
Laurence A. Boxer Research Professor of Pediatrics and Communicable Diseases
Pediatric Medical Director, Hemophilia and Coagulation Disorders Program
Director, Special Coagulation Laboratory
University of Michigan

MedicalResearch.com: What is the background for this study?

Response: Hemophilia B is an inherited bleeding disorder where patients are missing clotting factor IX (9), a critical blood clotting protein.  Patients with a severe deficiency are at risk for traumatic and spontaneous bleeds – primarily into joints.  Repeated bleeding into joints causes more than acute pain and swelling but also leads to inflammatory and degenerative changes in joints that eventually leads to severe debilitating arthritis that can be crippling.  To try to prevent this, patients as young as infants are placed on regular infusions of clotting factor IX concentrates.  The relatively short half-life of factor IX means patients must infuse on average once to twice a week.  These can only be delivered intravenously – parents and then patients themselves have to learn this.  Prophylaxis must be continued lifelong to try to prevent bleeding events and protect joint health over the lifespan.  This is a tremendous burden on the patient and their caregivers.

Even with regular prophylaxis, joint bleeds may still occur and arthropathy may still ensue.  This is because the blood levels often reach critically low levels prior to the next infusion.  Gene therapy aims to deliver a functional copy of the factor IX gene such that the patient’s own liver will make a continuous supply of factor IX that is delivered to the bloodstream.  At steady state with levels close to or within the normal range, patients would no longer be subject to bleeding events and would not require prophylaxis any longer.  We hope that such a one-time treatment would produced durable, “functionally curative” levels of factor IX.

MedicalResearch.com: What are the main findings?

Response: The 3 key takeaways are:

1. This study is the first phase 3 study to report findings on their entire cohort of subjects.  It is also the largest cohort of subjects who have received gene therapy for hemophilia to report to date.
2. Uses an adeno-associated virus vector (AAV5) that has had the viral genes replaced with a functional copy of the human factor IX gene that has been enhanced by a naturally occurring point mutation that codes for a hyperactive form of factor IX, this boosts the effective activity of factor IX in the blood plasma by 6 to 8-fold.  The vector is delivered as a single IV infusion in the outpatient setting and with a couple of weeks, factor IX expression is sufficient to protect from bleeding.  Subjects in the trial have achieved a mean factor IX activity of 37% 26 weeks following dosing – (with non-hemophilic range starting at 40%).  Levels have remained stable over the course of the study with the longest follow up being 18 months.  These levels allowed the patients who achieved transduction to cease prophylaxis for the duration of the follow up period.  The number of treated bleeds fell by 91% compared to a 6 month lead in period when all patients were on prophylactic FIX infusions.
3. All AAV-mediated liver-directed gene therapy trials to date have excluded patients with pre-existing neutralizing antibodies to AAV which appear presumably due to natural exposure over the course of their life.  However, preceding Phase 1 and 2 studies suggested that pre-existing antibodies to this AAV5 would not impact transduction, so although patients were tested, they received dosing anyway.  The results show effective transduction in patients who had antibody titers as high as 678.  >42% of the subjects had pre-existing neutralizing antibodies and these had no correlation with any safety or efficacy parameters.

MedicalResearch.com: What should readers take away from your report?

Response: I think it is best to characterize this as a treatment that liberates patients with hemophilia from the burden of repeated prophylactic infusions of clotting factor to protect them from recurrent bleeding events.  Gene therapy offers a chance to have steady state levels of factor in the blood that would eliminate risk for spontaneous and even traumatic bleeding events.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: These are very encouraging results – maximizes eligibility for patients by being able to treat in the presence of pre-existing neutralizing antibodies.  Results are in a range that allow for cessation of prophylaxis and continued bleed protection.  Results appear to be durable through the follow up period to date.  The 26 week endpoint was a co-primary endpoint.  The other endpoints are factor IX activity at 52 weeks and annualized bleeding rate over the 52 weeks post-dosing.  Those endpoints should be analyzed in 2021 and decisions could then be made on submission for regulatory review.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: This could be potentially clinical practice changing, if approved.  This looks to be a transformative therapy for patients and could be an option for patients across the adult lifespan – we treated patients from age 19 through 75.  Our patient population have been looking forward for a long time for a one-time therapy like this that would provide lasting protection from bleeds.

I have served as a paid consultant to uniQure and chair the Steering Committee for the global clinical trial program

Citation: ASH2020 Oral Abstract

First-in-Human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A – BAY 2599023 has Broad Patient Eligibility and Stable and Sustained Long-Term Expression of FVIII

Steven W. Pipe, MD¹, Francesca Ferrante, MD^2*, Muriel Reis^3*, Sara Wiegmann^4*, Claudia Lange^5*, Manuela Braun^5* and Lisa A Michaels^{6*
https://ash.confex.com/ash/2020/webprogram/Paper139803.html}

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Last Updated on December 8, 2020 by Marie Benz MD FAAD