Interview: how has the first gene therapy for hemophilia B transformed research?

Photo/Elena Resko
Hemophilia B gene therapy

Hemophilia B, a rare disease that affects more than 230,000 people worldwide is caused by the lack of or defective clotting protein factor IX often due to a spontaneous mutation in the F9 gene, leading to excessive bleeding.

Until recently, routine prophylactic infusions of factor IX replacement therapy to maintain enough clotting factor to prevent excessive bleeding, was administered to patients. The treatment has been considered to have a significant impact on the quality of life of hemophilia B patients as they’ve had to adhere to stringent, lifelong infusion schedules. 

A recent advancement in hemophilia research has led to the possibility to eliminate the need for lifelong, routine prophylactic treatments. CSL Behring’s Hemgenix, the first-ever one-time gene therapy for hemophilia B patients was approved by the European Commission in February 2023. This was following the U.S. Food and Drug Administration’s (FDA) approval in November 2022.

We interviewed Lutz Bonacker, senior vice president and general manager of Commercial Operations Europe at CSL Behring to find out how this therapy has transformed research in hemophilia B, and research in rare diseases at large.

How is Hemgenix a one-time life-long treatment for hemophilia B patients?

Hemgenix (etranacogene dezaparvovec), which received Conditional Marketing Authorization (CMA) from the European Commission on February 20, 2023, is the first and only one-time gene therapy for the treatment of severe and moderately severe hemophilia B (congenital Factor IX deficiency) in adults without a history of Factor IX inhibitors.  

Current treatment includes ongoing, routine prophylactic infusions of Factor IX to temporarily replace or supplement low levels of the blood-clotting factor, which places a life-long burden on patients, caregivers and healthcare systems.

Following the infusion of Hemgenix, 96% of patients discontinued FIX prophylaxis as they demonstrated stable and durable increases in mean FIX levels (mean is 36.9%) which led to annualized bleed rate (ABR) reduction of 64%.  These findings come from the pivotal HOPE-B study which showed that Hemgenix not only demonstrates non-inferiority but also demonstrates superiority to prophylaxis treatment at 18 months post treatment compared to a run-in period.   

Further to this, the HOPE-B study 24-months analysis showed a sustained and durable effect of Hemgenix. 

The specific obligations linked to the CMA status require us to provide 5-year follow-up data from patients who received Hemgenix  during phase 2b and phase 3 HOPE-B clinical trials. We have also committed to sharing the 1-year post infusion data from the first 50 commercially treated patients enrolled in our phase 4 Study (now categorized as a post-approval efficacy study).

When did the Hemgenix trials begin?

We began the HOPE-B clinical trial for Hemgenix on June 27, 2018.

Were there any side-effects noticed among patients to the drug?

The HOPE-B data demonstrates that in a clinical setting, Hemgenix continues to be generally well-tolerated with no serious treatment-related adverse events (AEs). 

In terms of safety: there were no treatment related serious AEs in the pivotal study. The most frequent AEs were headache (31.6%), ALT elevation (22.8%), AST elevation (17.5%) influenza-like illness (14%) and infusion related reactions (12.3%).

Is the annualized bleed rate different in patients who were administered Hemgenix when compared to routine prophylactics?

Yes, after the six-month lead-in period post-infusion, the adjusted annualized bleed rate for all bleeds was reduced by 64%, demonstrating non-inferiority and superiority of Hemgenix as compared with factor IX prophylaxis.

How has Hemgenix gene therapy transformed hemophilia research?

We are proud that Hemgenix has demonstrated the potential to transform the treatment paradigm for adults living with severe or moderately severe hemophilia B. This is through providing elevated and sustained Factor IX levels, improving bleed protection, eliminating the need for patients to undergo routine prophylactic infusions and reducing the high treatment burden and medical care required. 

The treatment therefore has the potential to fulfill a significant unmet medical need among adults with severe and moderately severe hemophilia B, who currently live with the burden of routine, regular prophylactic infusions. 

When will the gene therapy be made commercially available now that it has been approved by the EC?

We are committed to working to enable patient access to gene therapy and will collaborate with all stakeholders, including the medical, payer and patient community, to find the best solutions to enable access and adequate healthcare delivery to patients who can benefit from this transformative innovation.  Hemgenix will first be made available in 2023 in Germany, followed by other European countries.

Will all hemophilia B patients be able to receive the gene therapy? Are there patients who cannot be given the drug due to side-effects, allergies or other issues?

Hemgenix is indicated for the treatment of severe and moderately severe hemophilia B in adult patients without a history of Factor IX inhibitors. Before administration of Hemgenix baseline testing is required. 

Contraindications include hypersensitivity to the active substance, active infections and patients with known advanced hepatic fibrosis, or cirrhosis. Full information will be available in the Summary of Product Characteristics published by the EMA.

In a clinical setting, Hemgenix continues to be generally well-tolerated with no serious treatment-related adverse events.

Is it something that is going to be available to anyone suffering from this condition? What would the cost be and would the drug be accessible to people from various economic backgrounds?

Hemgenix is indicated for the treatment of severe and moderately severe hemophilia B in adult patients without a history of Factor IX inhibitors. Hemophilia B is a rare disease, occurring in approximately 1 in 25,000 male births and affecting an estimated 5,900 people in Europe.

As the first gene therapy for severe and moderately severe hemophilia B, Hemgenix will be priced in line with the high clinical and economic value it brings to eligible patients, healthcare systems and society. In Europe, access and pricing pathways will differ across countries and the price of Hemgenix will be negotiated and agreed in close collaboration with governments and payers at national level.

Where is the therapy on its journey in other places such as the U.S. and the Asia Pacific region?

Hemgenix was approved by the U.S. Food and Drug Administration (FDA) in November 2022 for the treatment of adults with hemophilia B who currently use factor IX prophylaxis therapy or have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes. 

At present, the therapy is not currently approved outside of the U.S. and Europe.

Does this have any other potential applications in other conditions, and does the company have anything else in the pipeline?

Our primary focus is to support the launch for patients with severe and moderately severe hemophilia B, working with governments and payers to prepare adequate pathways for access, pricing, and reimbursement, as well as ensure healthcare system readiness to identify eligible patients, administer treatment and ensure long term follow up.

Beyond this, we are going to continue the legacy we have built over the past century, by remaining focused on developing and delivering essential and innovative medicines to patients and populations all over the world.

How would you describe this advancement in gene therapy for rare disease research?

The goal of gene therapy in hemophilia B is to provide long-term benefits, with sustained factor IX activity at near-normal levels, from a single administration of treatment. In this way, gene therapy aims to reduce or even eliminate spontaneous bleeding and the need for routine prophylactic infusions. 

The approval of Hemgenix in Europe is a huge milestone as it demonstrates the potential of innovative scientific developments, such as that of gene therapy, to truly impact and change the lives of patients suffering from rare diseases and the burden of ongoing, lifelong treatment.

Now we need to work to ensure that as many eligible patients across Europe can access this innovative treatment as possible. We are fully committed to working together with payers and other stakeholders to achieve this.

How will this influence the progress of research of other rare diseases? 

As we better understand the unique needs of people affected by rare disease, we can progress research even further and better support patients who have previously had very limited treatment options. Therefore, we are now at a pivotal stage in envisioning the future of treatment for a wide range of serious diseases.

Gene therapy research for clinical applications has been ongoing for over 50 years, with more than 2,500 active clinical trials in genetic therapy research currently being undertaken.

Continued advances have seen several gene therapies approved for single-gene replacement, while, more recently, other approaches use cutting-edge technology to fix errors within genes.

It is a truly momentous time to be a part of gene therapy innovation and research, and to witness the potentially life-changing impact these therapies can have for patients living with rare disease and their loved ones.

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