Haemophilia is caused by mutations in the genes encoding coagulation factor VIII (FVIII) or IX (FIX) [1]. The current standard of care for people with severe haemophilia is life-long prophylaxis with recombinant or plasma-derived coagulation factor concentrate, representing considerable treatment burden without eliminating the risk of bleeding [1, 2]. In addition, development of inhibitors to the administered coagulation factor concentrate may complicate treatment [3]. In the last 13 years, adeno-associated virus (AAV)-based gene therapy for haemophilia, which involves the transfer of genes for FVIII or FIX to target cells following a single infusion, has advanced substantially [2, 4]; the aim of which is to enable long-term endogenous coagulation factor production [4]. After haemophilia gene therapy, patients have reported improvements in their quality of life, bleeding rate and physical activity, as well as more freedom [5]. Although this suggests that gene therapy could have a positive impact on the lives of patients living with haemophilia, there are numerous other aspects that are essential to consider.

Positive outcomes have been reported in Phase 3 trials of three products. In 132 adult males with haemophilia A, the GENEr8-1 study showed that valoctocogene roxaparvovec increased FVIII activity from baseline (when participants were receiving FVIII prophylaxis) to Month 24 post-treatment by a mean of 22.0 IU/dL and 35.1 IU/dL using chromogenic and one-stage assays, respectively [6]. Additionally, mean annualised FVIII concentrate consumption decreased by 98.2% and mean annualised rate of treated bleeding episodes was reduced by 84.5% from baseline (n = 112). In the HOPE-B study, 54 adult males with haemophilia B were treated with etranacogene dezaparvovec following a ≥ 6-month lead-in period with FIX prophylaxis [7]. Annualised bleeding rate reduced from 4.19 during the lead-in period to 1.51 post-treatment (Months 7–18) and was sustained at Month 24; 96.3% of study participants stopped and remained free from prophylactic FIX therapy over 24 months post-treatment [7, 8]. At Months 6 and 24, mean FIX activity levels increased to 39.0 IU/dL and 36.7 IU/dL, respectively [7, 8]. Positive outcomes were also reported from the Phase 3 BENEGENE-2 trial investigating fidanacogene elaparvovec in adults with haemophilia B, with relatively stable FIX activity levels observed at Month 24 in the 22/45 patients for which data were reported; mean FIX activity level using the one-stage SynthASil assay was 25.0% in these patients [9].

In August 2022, valoctocogene roxaparvovec (ROCTAVIAN™; BioMarin Pharmaceutical Inc.) received conditional approval from the European Commission (EC) for use in adults with haemophilia A; approval by the US Food and Drug Administration (FDA) followed in June 2023 [10, 11]. In November 2022, etranacogene dezaparvovec (HEMGENIX®; CSL Behring) received FDA approval for use in adults with haemophilia B, before conditional approval by the EC and UK Medicines and Healthcare products Regulatory Agency (MHRA) in early 2023 [12,13,14]. In October 2023, Health Canada authorised etranacogene dezaparvovec [15], which was followed by authorisation by Swissmedic in January 2024 [16]. In December 2023, Health Canada approved fidanacogene elaparvovec (BEQVEZ™; Pfizer Canada ULC) for use in adults with haemophilia B [17].

Despite positive outcomes, challenges remain, and the pharmaceutical industry is focused on facilitating wider treatment access for haemophilia patients. Valoctocogene roxaparvovec, etranacogene dezaparvovec and fidanacogene elaparvovec are approved for use only in adults without factor inhibitors [10,11,12,13, 17]. Animal models suggest that AAV-based gene therapy for haemophilia A has the potential for induction of immune tolerance to FVIII [18]. Of note, a study evaluating valoctocogene roxaparvovec in patients with severe haemophilia A and FVIII inhibitors is in the recruitment stage (NCT04684940) [19].

Although it has been shown that pre-existing anti-AAV neutralising antibodies (NAbs) can impair therapeutically useful vector delivery [20], the presence of these antibodies (up to a titre of 678) did not affect treatment efficacy with etranacogene dezaparvovec [7]. Research is still ongoing within this area for valoctocogene roxaparvovec and currently this product is only indicated for use in patients without pre-existing anti-AAV5 NAbs [6, 10, 11]. Similarly, Health Canada has only approved the use of fidanacogene elaparvovec in patients without anti-AAV NAbs [17].

The extent of transgene expression can vary between patients [20]; monitoring of coagulation factor levels is needed post-treatment [10,11,12,13, 17]. The three licensed products have associated risks of liver toxicity, which may be accompanied by reduced expression of the transgenic protein; this requires post-infusion monitoring of liver enzymes and potentially corticosteroid treatment, introducing further risk of adverse events [10,11,12,13, 17, 20]. Cytotoxic T-cell responses against the AAV capsid is one suggested explanation for this hepatotoxicity [20]. Although it is thought that AAV vectors remain mostly episomal in the nucleus, vector integration can occur and it is unknown whether there is an increased risk of genotoxicity [2, 20]. Larger, long-term follow-up studies will be essential for gaining a more comprehensive understanding of the outcomes and safety of gene therapy [20, 21], and partnerships across industry, patient organisations and regulatory authorities will be crucial for their success [21].

It is important to note that gene therapy has not been studied in children with haemophilia [20], but paediatric investigation plans have been agreed by the European Medicines Agency [22,23,24]. The use of gene therapy in young people could avert long-term morbidity by preventing bleeds from an early age [20].

A further consideration is the cost of haemophilia gene therapy. Alternative payment models have been proposed due to the associated clinical and economical unknowns; introduction of these new methods will require engagement of all stakeholders [25]. One such model is outcome-based contracting, which involves the reimbursement of costs if expected outcomes are not met, thereby achieving value for patients [25,26,27].

Lastly, AAV-based gene therapy is irreversible and a one-time only treatment due to priming of the recipient’s immune system to the vector [21, 28]. Thus, patient expectations must be thoroughly explored in order to prevent “buyer’s remorse”, for example in the scenario of products becoming inferior to newly developed AAV vectors [21, 28].

During the CSL Behring-sponsored symposium at the 27th Congress of the European Hematology Association (EHA) 2022 in Vienna, Austria, Ingrid Pabinger (Symposium Chair, haematologist), Wolfgang Miesbach (haematologist), Greta Mulders (nurse) and Daan Breederveld (haemophilia patient and occupational health physician) described gene therapy from a 360-degree perspective of the haemophilia multidisciplinary team (MDT). A 360-degree perspective allows individuals involved in patient care to have oversight of the patient journey and of each MDT member’s role. In this review, the faculty summarised their own viewpoints from the symposium, focusing on the importance of the 360-degree perspective, the expectations and unknowns of gene therapy and the practical steps needed for gene therapy delivery. This review aims to highlight the key considerations required to engage with gene therapy effectively, for both patients and providers, as well as the importance of multidisciplinary collaboration, including with industry.

Gene therapy in practice: The 360-degree perspective

The introduction of gene therapy will significantly impact the care that haemophilia patients require [29]. Initially, the decision arises of whether gene therapy is right for each individual patient. The MDT must ensure the patient is at the centre of the shared decision-making process and that education and counselling are available to each individual [29, 30]. In addition, the practicalities of administering gene therapy, including pre- and post-treatment assessments and product infusion, differ from current therapies [21].

Gene therapy necessitates multidisciplinary care, incorporating key roles for treating physicians, nurses, physiotherapists and psychologists, and additional specialities such as hepatologists [30, 31]. As such, an integrated approach is advocated, ensuring the required level of care is delivered efficiently at each stage of the patient journey [29]. The hub-and-spoke model may facilitate this when a patient lives at a distance from a haemophilia treatment centre (HTC) that is experienced in gene therapy. In this model, the hub is an HTC that prescribes and manages gene therapy and the spoke is an HTC without gene therapy experience, where pre- and post-infusion monitoring is performed; the model requires close communication between the two and sets a new precedent in the standard of haemophilia care [21, 30]. The haemophilia community within their national member organisations and societies, pharmaceutical industry and payers are also key partners throughout the process, providing further support via delivery of shared decision-making tools (e.g., The World Federation of Hemophilia Shared Decision-Making Tool [32]) and educational materials [29].

Herein, the authors present their opinions around the key concepts presented during the symposium at EHA 2022.

Why is a 360-degree perspective important in gene therapy patient care?Physician (Wolfgang Miesbach writes…)

With the introduction of novel treatment options, multidisciplinary care has become even more crucial. Gene therapy requires the involvement of specialities who may not have been routinely involved in haemophilia care and responsibilities and tasks may need redefining.

During the pre-administration period, relevant stakeholders should be involved in determining patient eligibility for treatment. For example, liver health status should be assessed by a hepatologist [21, 31]. Following administration, increased levels of inflammatory markers of the liver (alanine aminotransferase [ALT] elevation) require close monitoring and may necessitate corticosteroid administration to preserve transgene expression [31]. Corticosteroid therapy involves careful management to minimise the risk of adverse events [31], including tapering of doses to avoid secondary adrenal insufficiency from long-term use [33]. Furthermore, patients with pre-existing anti-AAV NAbs or those experiencing cytotoxic T-cell responses following treatment may require advice from an immunologist.

Prior to gene therapy treatment, psychologists play a vital role in exploring patient motivation for receiving gene therapy [30]. Furthermore, they can support patients who may be ineligible for gene therapy, have a lack of response or experience a loss of identity following an improvement in their disease.

As gene therapy may not only affect the patient themselves, the decision-making process should also involve caregivers and/or families. Family members may be best placed to provide a true picture of the patient’s current situation, and discussions should reflect on the existing treatment landscape and how the current approach to gene therapy would fit into the patient’s lifestyle.

Nurse (Greta Mulders writes…)

The haemophilia nurse has a central role in providing guidance and follow-up care, not only to those receiving gene therapy, but to all patients with haemophilia [34, 35]. As well as their clinical care skills, haemophilia nurses have specialist clinical knowledge and can provide support to patients and their families in a collaborative manner [34]. As nurses often have the first contact with patients, a nurse-patient relationship based on trust can be developed, with support/follow-up tailored to individual needs [34].

As the treatment landscape evolves, the provision of patient care is also transforming [29]. Healthcare providers often adapt to new strategies, technologies and procedures quickly, yet patients may not be as resilient in handling these changes, resulting in missed opportunities for patients to obtain a holistic view of their needs. A 360-degree perspective of the team members involved in patient care is key, enabling the MDT to have a full understanding of the patient journey. This allows each member of the MDT to engage the patient with the right message at each stage of their healthcare journey, using the most appropriate channels and suitable level of detail for the patient. One of the simplest ways healthcare professionals (HCPs) can increase patient engagement is to tailor the way they communicate to suit each individual patient. Published research has demonstrated that increased patient engagement leads to improved outcomes [36]. In some centres, patients may be included in multidisciplinary meetings; a UK Government response on the ‘Liberating the NHS: No decision about me, without me’ consultation provided various suggestions to increase patient involvement in the care process [37]. Effective involvement of the patient requires good communication with their healthcare professionals and may increase treatment compliance.

Patient (Daan Breederveld writes…)

In the current healthcare landscape, the patient perspective is of growing importance, especially for the success of gene therapy (Fig. 1). With the increasing use of various types of media due to global technological advancements, information is now available to a wider proportion of the population than ever before; however, not all sources are necessarily reliable. In addition, patient attitudes towards HCPs are increasingly critical; general acceptance of any medical treatment by patients is dependent on a well-informed team of HCPs with excellent communication skills.

Fig. 1

Why is the patient perspective on gene therapy important? From the perspective of the patient, gene therapy is a one-off, irreversible treatment that requires careful consideration. Factors in the success of gene therapy include improvement on the current standard of care and quality of life, as well as long-term reliable, sustainable, and predictable outcomes. QoL, quality of life; SOC, standard of care

A patient’s decision of whether to undergo gene therapy may be influenced by the current standard of care and disease burden, which varies significantly between countries and patients. Furthermore, psychological, cultural and/or religious aspects may influence a patient’s attitude towards gene therapy. As gene therapy is a one-off, irreversible treatment [20, 21], the decision-making process can take both time and effort from all involved. It is unlikely that patients will be able to manage this by themselves; I required support from my MDT, family, social and professional networks. The possibility that I would no longer be dependent on regular therapy to live was a major contributor to the decision-making process.

The challenge for gene therapy is to offer long-term, sustainable results [38]. Considering this and other uncertainties (e.g., short- and long-term side effects), patients must be provided with all pros and cons of treatment. This represents an unprecedented challenge in haemophilia care and emphasises the need for a new approach.

From your perspective, what are your expectations for before/during/after gene therapy, and how should these be managed?Physician (Wolfgang Miesbach writes…)

The major challenges surrounding gene therapy management for HTCs are summarised in Fig. 2. Firstly, patients and HCPs should be aware that any changes to the patient’s eligibility since the initial assessment could affect whether gene therapy can be administered. During administration, infusion-related reactions (IRRs), such as hypersensitivity reactions and fever, are possible [2, 6, 7]; patients should be informed about the risk of these occurring and physicians should have access to relevant guidelines. If IRRs occur, the balance of efficacy and safety must be considered. These reactions may be managed by prematurely stopping the infusion; however, this could result in inadequate treatment and may prevent the patient from receiving gene therapy in the future [2, 7, 20]. It is also important to consider that some effects may be related to anxiety surrounding the situation and not the gene therapy itself.