Gene therapy landmark in haemophilia B

Following the news that the first patients in Denmark with haemophilia B had been treated with Hemgenix (etranacogene dezaparvovec) gene therapy since European Commission approval, DDW’s Megan Thomas spoke with Dr Fredrik Sjöö, Head of Medical Affairs in the Nordic Region at CSL Behring, as well as Radovan Tomic, Global Market Access Director at CSL Behring. MT: What does the treatment of patients with Hemgenix signify for the broader adoption of gene therapy in haemophilia B? FS: The first patients in Denmark to receive Hemgenix (etranacogene dezaparvovec) marks a historic moment for the haemophilia B community in Denmark and follows the first patients treated in Europe in July 2024. Patients in Denmark can access Hemgenix through an innovative outcome-based agreement with Amgros, finalised in October 2024. This makes Denmark the first Nordic and European country to adopt a performance-based model, where costs are incurred only as long as the gene therapy proves effective over the agreed long-term period, this is also the first permanent complete agreement in Europe on public funding of gene therapy for haemophilia B. We are continuing to build positive momentum for Hemgenix, and we are seeing increased interest and activity among healthcare professionals and patients. We are confident in the long-term value of Hemgenix for people with haemophilia B and healthcare systems across the world. We are actively engaging in a number of ongoing discussions with stakeholders in European and international markets to expand access. Innovative access solutions, such as the performance-based model adopted by Denmark, could pave the way for the broader and sustainable adoption of gene therapy and for eligible people with haemophilia B in other countries to access Hemgenix. MT: How has the development of Hemgenix demonstrated the potential of gene therapy to transform drug discovery and treatment strategies? FS: Seventy-two years ago, it was discovered that inherited haemophilia B is caused by a genetic defect that deprives the liver of the capacity to produce enough functional Factor IX. Today, treating haemophilia B by restoring this capacity to the liver has become part of clinical practice in Denmark. The success of Hemgenix regulatory approvals and reimbursement agreements may encourage further research and development in gene therapy, leading to more innovative treatments for other genetic conditions. Gene therapy has the possibility to transform many aspects of the treatment paradigm, as it represents the potential of a single-infusion one-time treatment option, which may lead to a reduction in the time and resources required to treat many genetic conditions, such as haemophilia B. Hemgenix is leading the way with landmark reimbursement agreements that allow patients to benefit from this transformative treatment option. MT: What were the biggest challenges in developing and gaining regulatory approval for Hemgenix, and how were they overcome? RT: With pioneering treatments such as cell and gene therapies (CGTs), there are always going to be challenges and hurdles to overcome ahead of launch, which is why early collaboration with regulators, health technology assessment (HTA) bodies, payers, clinicians, and patients is so important. Many national regulatory and HTA agencies need to make adjustments to their models and methods to ensure they can fairly assess one-infusion treatments and their projected long-term durability. In the example of Denmark, a new Danish Advanced Therapy Medicinal Product approvals process was established in May 2024. CSL Behring worked in close collaboration with the Danish Medicines Council and Amgros to develop an outcome-based agreement for Hemgenix which was suitable for this new process. CSL Behring believes through close collaboration, alternative payment models can provide real value to the patients, the healthcare professionals, and healthcare systems worldwide. However, the implementation of these critical contracts and innovative agreements may take time, and require effort and flexibility from both sides, as healthcare systems can face challenges in identifying practical solutions based on their local regulatory and access systems. We are proud to be working on joint solutions to address the challenges with current HTA frameworks in assessing innovative therapies. MT: How does the outcome-based agreement in Denmark set a precedent for future CGT market access models? FS: One of the main challenges was reaching a consensus on both the extent of the risk for loss of efficacy beyond the current duration of clinical Phase IIb and Phase III trials, and determining suitable price adjustment for this risk. It became evident early on that an outcome-based agreement would be beneficial in addressing this issue. Countries like Denmark are demonstrating how innovative access solutions could pave the way for patients in other countries to access HEMGENIX. Flexible contracting solutions, such as outcome-based agreements supported by real-world evidence, can allow sustainable and affordable payment options for patients and healthcare systems. We are proud to be working on joint solutions to address the challenges with current health technology assessment (HTA) frameworks in assessing transformative, one-time therapies. We have reached milestone funding agreements in the past year with Austria, the UK (England and Scotland), Denmark, Spain, and Switzerland. Thanks to these innovative access decisions, eligible people living with haemophilia B will be able to benefit from Hemgenix. We are confident in the long-term value of Hemgenix for people with haemophilia B and healthcare systems worldwide. We are actively engaging in a number of ongoing discussions with stakeholders in European and international markets to expand access. MT: What lessons from the development of Hemgenix could be applied to accelerating drug discovery in other rare diseases? FS: Haemophilia is often seen as a case study for gene therapy in the rare disease space, through which we can see the potential of this innovative treatment to give patients living with these conditions a new level of freedom. In the case of haemophilia, gene therapy has the potential to provide patients with freedom from bleeds, freedom from the burden of lifelong treatment, and freedom of mind (i.e. they no longer have to constantly think about their disease). It’s exciting to know that the successes of gene therapy in haemophilia can provide an example and pave the way for innovations in other rare disease areas. MT: How does Hemgenix’s mechanism of action compare to other gene therapies in development for haemophilia and beyond? FS: While we cannot comment on another company’s product, Hemgenix (etranacogene dezaparvovec) is the first one-time gene therapy approved for eligible patients with haemophilia B. The treatment consists of an engineered non-pathogenic adeno-associated virus (AAV) 5 vector carrying a Padua Factor IX gene, a rare and naturally occurring but highly active Factor IX gene that allows people to generate Factor IX proteins that are five to eight times more active than normal. Following infusion, which commonly takes as little as one to two hours, the vector delivers the Padua Factor IX gene to specific cells. Hemgenix has been carefully designed to target the liver to permit the liver cells to use the new genetic information and to produce its own functional Factor IX proteins. There are many different types of AAV vectors that can target specific areas of the body. AAV5 was chosen for Hemgenix because fewer people have pre-existing neutralising antibodies against AAV5 than several other AAV vectors, such as AAV2, which is quite common in humans. MT: How do you see the future of CGT evolving in terms of scalability, affordability, and accessibility? FS: There are three key factors that we see as imperative to evolving the scalability, affordability, and accessibility of gene therapy, which we are already seeing through our regulatory discussions for Hemgenix: Recognition of unmet needs: Healthcare systems understand and recognise the unmet needs of patients that gene therapy can address. Innovative payment models: Healthcare systems are willing and able to engage in alternative, truly innovative payment and contracting models. Specialised infrastructure: Healthcare systems invest in specialised infrastructure, resources, and capabilities to facilitate the appropriate administration of gene therapy and ensure optimal patient care, from diagnosis to long-term follow-up. Each country has its own unique healthcare system, requiring a tailored access pathway. However, many of these countries share a common openness and agility to pilot pioneering funding solutions, paving the way for patients to access gene therapies, such as Hemgenix. We are in continuous dialogue with healthcare authorities and insurance providers to ensure Hemgenix is included in national healthcare systems for all markets where we have secured regulatory approvals. In Denmark, our close collaboration with the Danish Medicines Council and Amgros was critical to developing an innovative outcome-based agreement ensuring patient access to this ground-breaking treatment and establishing a performance-based model. Now that Hemgenix is available to patients in Denmark, we are working closely with physicians to support the implementation of the risk management programme and communicate important new data as it becomes available. Hemgenix requires the implementation of new processes and systems at hospitals for ordering tests of AAV5 neutralising antibodies and ordering Hemgenix, it is part of our commitment to work with local authorities, treatment centres and patient organisations to provide timely and effective support to establish local gene therapy pathways. MT: Beyond haemophilia B, what other disease areas could benefit most from the breakthroughs seen in the development of Hemgenix? FS: Whilst gene therapy is still a new treatment option, research has been ongoing for over 50 years with more than 2,000 clinical trials in genetic therapy research taking place. These have resulted in several therapies being approved in Europe for diseases such as spinal muscular atrophy, retinal dystrophy (a type of vision loss), sickle cell disease, and haemophilia. These treatments have been shown to have a durable benefit to patients, demonstrating the potential to significantly reduce or eliminate symptoms and the need for patients to undergo lifelong treatment. MT: Do you think this illustrates opportunity for success in the CGT market in Denmark? FS: This is a truly historic moment for the haemophilia B community in Denmark. Eligible patients in Denmark can now move away from lifelong prophylactic injections, which place significant burden on people living with haemophilia B and can negatively impact their quality of life. By adopting a performance-based agreement for Hemgenix, Amgros is actively implementing innovative measures to ensure that eligible patients with high unmet need can access treatments they could benefit from. We are proud to have worked together with Amgros to pave the way for future innovative therapies in Denmark. Biographies Dr Fredrik Sjöö is the Head of Medical Affairs, Nordic region at CSL Behring. As a physician specialising in haematology, Sjöö has over a decade of experience as a haematologist, having worked at both Karolinska and St Görans Hospital in Stockholm. He holds a PhD from Karolinska Institute. Prior to joining CSL Behring, Sjöö worked in global safety at Novo Nordisk in Copenhagen. Radovan Tomic is Global Market Access Director at CSL Behring, covering haemophilia B gene therapy across International Markets. With extensive experience in global market access and hematology, Radovan leads strategic initiatives to enhance patient access to innovative therapies. Radovan's expertise and dedication drive impactful results in the healthcare industry.