Clinical experience of switching patients with severe hemophilia to rVIII-SingleChain or rIX-FP

Abstract

Objective

Prophylaxis treatment is the current standard of care for patients with severe hemophilia. Factor concentrates with improved pharmacokinetics have offered more options for individualizing treatment. The treatment focus may be on increased protection, aiming for higher trough factor levels or longer dosing intervals to reduce the burden of hemophilia. Both aspects can have long-term effects on joint health. Products, such as rVIII‑SingleChain and rIX-FP have been developed to reduce the treatment burden for patients with hemophilia and optimize prophylactic efficacy. The objective of this report is to provide a summary of the clinical experience of different Hemophilia Treatment Centers in managing the switch to rVIII-SingleChain or rIX-FP in patients with hemophilia.

Methods

This report summarizes a selection of patient cases presented at the 3rd Alliance for Coagulation Academy Meeting in October 2020. The cases from the participating centers provide examples of the clinical experience in managing patients’ switch to rVIII-SingleChain and rIX‑FP, including which types of patients are suitable for switching, and practical steps in managing a switch.

Results

It is important to take into consideration the physical and social fulfillment of the patient when deciding to switch to rVIII-SingleChain or rIX-FP. The physician plays an important role in the motivation of patients as they understand not only the patient's needs but the potential benefits of the new treatment.

Conclusion

The selected patient cases reported here demonstrate that patients may wish to switch factor products for a variety of reasons; therefore, it is critical to understand why patients switch and what they expect from switching.

Keywords:

• Hemophilia A
• hemophilia B
• factor IX
• factor VIII
• rIX-FP
• rVIII‑SingleChain
• switch

Introduction

Hemophilia is a rare recessive X-linked congenital bleeding disorder defined by a deficiency of clotting factor VIII (FVIII), known as hemophilia A, or factor IX (FIX), known as hemophilia B¹. Hemophilia is characterized as an excess in bleeding; in severe cases, it is defined by spontaneous bleeding, primarily into joints (hemarthroses) which can cause chronic pain and long-term joint damage¹. The primary goal for treatment is to prevent/treat bleeding events with factor replacement and prophylaxis with factor replacement therapy is currently the recommended standard of care for the treatment of hemophilia^1–3. The original goal for prophylaxis was to maintain FVIII/FIX trough levels >1% to prevent spontaneous or traumatic bleeds and to promote healthy joints, as increasing time spent with factor levels <1% is associated with an increased rate of breakthrough bleeds⁴. However, the World Federation of Hemophilia (WFH) and European guidelines now recommend minimum FVIII/FIX trough levels of 3–5%^1,2. Standard-acting FVIII products with a half-life of 8–12 h in adults often require 3–4 infusions per week to maintain trough levels >1% and prevent breakthrough bleeding¹. Patients with hemophilia A who infuse with a mean of 3.5 infusions a week have a yearly intravenous injection rate of 182, excluding any additional infusions for breakthrough bleeds. Standard-acting FIX products have a half-life of 18–24 h in adults, necessitating 2–3 infusions per week¹. Patients with hemophilia B who have a mean of 2.5 infusions a week have a yearly infusion rate of 130. The combination of low trough levels and poor adherence due to the high treatment burden can have a long-term impact on joint health.

Factor products with improved pharmacokinetic (PK) profiles allow treatment to be individualized to reduce the treatment burden, potentially leading to more efficient protection against bleeding^3,5,6; examples of these products include rVIII-SingleChain and rIX-FP^7–9. When considering switching to rVIII‑SingleChain or rIX-FP there are three potential strategies: (1) maintain the same treatment regimen but use rVIII-SingleChain or rIX-FP to achieve higher FVIII/FIX trough levels, to give increased bleed protection due to the improved PK and pharmacodynamics (PD); (2) use the improved PK/PD of rVIII-SingleChain or rIX-FP to increase the dosing interval and reduce treatment burden; or (3) extend the dosing interval using rVIII‑SingleChain or rIX-FP but with an increased dose to provide increased bleed protection. It is important to also consider the physical and social fulfillment of the patient when deciding whether to switch to rVIII‑SingleChain or rIX-FP.

The objective of the article is to summarize the clinical experience of authors from five countries (France, Germany, Israel, Italy, and Switzerland) in managing the switch to rVIII-SingleChain (Table 1) or rIX-FP (Table 2) in patients with hemophilia. The selected clinical cases described below were presented at a meeting organized and funded by CSL Behring, the 3rd Alliance for Coagulation Academy Virtual Meeting (29–30 October 2020). The cases illustrate the types of patients who may be suitable for switching to rVIII‑SingleChain or rIX-FP and the practical aspects of managing this transition.

Table 1. Summary of the selected patients who switched to rVIII-SingleChain.

Country	Patient characteristics	Previous treatment	rVIII‑SingleChain prophylaxis regimen
Germany	18-year-old	pdFVIII (2000 IU, 3×/week); this provided a FVIII trough level of 0.5–1% after 72 h	2000 IU, 3×/week; this achieved a FVIII trough level of 3% after 72 h and a half-life of 15 h
Germany	Pediatric patient	pdFVIII (1000 IU 3×/week)	1000 IU, 3×/week
France	15-year-old	rFVIII (1500 IU, 3×/week); this provided a FVIII trough level of 3.1% after 48 h and a half-life of 11.1 h	1500 IU, 3×/week; this provided a FVIII trough level of 10.2% after 48 h and a half-life of 17.2 h. After 5 months, the regimen was changed to 2000 IU, 2×/week
Germany	60-year-old	rFVIII (2000 IU every 2 days, 100 IU/kg/week); this provided a 3-day FVIII trough level of 2.4%	3000 IU, 2×/week, 81 IU/kg; this provided a 3-day FVIII trough level of 6.7%
Italy	2-year-old	None [previously untreated patient]	35 IU/kg, 2×/week

FVIII: factor VIII; pdFVIII: plasma-derived factor VIII; rFVIII: recombinant factor VIII.

Table 2. Summary of the selected patients who switched to rIX-FP.

Country	Patient characteristics	Previous treatment	rIX-FP prophylaxis regimen
Germany	21-year-old	rFIX (2000 IU 3×/week); this provided a FIX trough level of 2% after 72 h	4000 IU, every 10 days; this provided a FIX trough level of 10% after 10 days and a half-life of 140 h
Italy	6-year-old	Standard-acting FIX (40 IU/kg 2×/week)	50 IU/kg, 1×/week
Italy	71-year-old	Episodic treatment with pdFIX	Post-operative regimen: 50 IU/kg, every 10 days. Prophylaxis regimen: 40 IU/kg, 1×/week; this provided a FIX trough level of 10%
Israel	16-year-old	pdFIX (40 IU/kg, 2×/week)	75 IU/kg, every 10 days
Switzerland	43-year-old	Episodic treatment with pdFIX	50 IU/kg, every 14 days

FIX: factor IX; pdFIX: plasma-derived factor IX; rFIX: recombinant factor IX.

Clinical experiences of switching patients with hemophilia a to prophylaxis with rVIII-SingleChain

rVIII-SingleChain (AFSTYLA^®, CSL Behring, King of Prussia) is a novel recombinant single-chain molecule with enhanced molecular stability and increased binding affinity to von Willebrand factor compared with standard FVIII^10,11. In addition, rVIII-SingleChain has an improved PK profile compared to standard-acting FVIII products¹⁰. In rats, the area under the curve (AUC) was increased ∼6-fold with rVIII-SingleChain compared with recombinant FVIII (rFVIII); similarly, the half-life was 2-fold higher with rVIII-SingleChain vs rFVIII, and clearance was 5-fold lower compared to rFVIII¹⁰. In humans, the AUC of rVIII-SingleChain was increased by 35% compared to a standard-acting FVIII and clearance was ∼39% lower with rVIII-SingleChain compared to standard-acting FVIII¹². The AFFINITY clinical trial program (phase I/III: NCT01486927, phase III: NCT02093897, phase III extension: NCT02172950) was designed to evaluate the safety, efficacy, and PK of rVIII-SingleChain in previously treated patients (PTPs) with severe hemophilia A. The clinical trial program demonstrated that the majority of patients treated with rVIII‑SingleChain have excellent hemostatic efficacy for both the prevention and treatment of bleeds and a favorable safety profile, with no inhibitors to FVIII developing in PTPs^7,13. At the end of the clinical trial in adult patients, 74% (89/121) were dosing between 2–3×/week with 20–50 IU/kg rVIII‑SingleChain⁷. Annualized bleeding rates (ABR) were low and annualized spontaneous bleeding rates (AsBR) were zero across all prophylaxis regimens in both adult/adolescent and pediatric populations^7,13. A sub-study of patients from the AFFINITY clinical trial program undergoing major surgery also demonstrated the efficacy of rVIII-SingleChain for the management of perioperative hemostasis⁷. Insights into the use of rVIII-SingleChain in routine practice have the potential to inform real-world evidence-based treatment decisions.

Clinical experience from Germany included three adult cases with severe hemophilia A, all of whom demonstrated better bleed protection and improved adherence following a switch to rVIII-SingleChain (Table 1). Factor consumption was unaffected by the switch, indicating that the improved bleed protection was due to the higher trough levels with rVIII-SingleChain compared to the previous products. One case was an 18-year-old who was previously treated with a plasma-derived FVIII (pdFVIII; 2000 IU, 3×/week) which provided an FVIII trough level of 0.5–1% after 72 h. Before switching, the patient was adherent and did not wish to change their regimen. However, a spontaneous joint bleed in the left elbow prompted a wish for better protection from spontaneous bleeds. The patient was switched to rVIII-SingleChain with the same regimen, dose, and consumption (2000 IU, 3×/week); this regimen achieved an FVIII trough level of 3% after 72 h and the half-life estimated with WAPPS-Hemo¹⁴ was 15 h. The patient experienced no further joint bleeds following the switch due to the increased bleed protection afforded by higher FVIII trough levels.

The benefits of switching to the same regimen and consumption with rVIII-SingleChain to improve adherence and provide efficient bleed protection were also demonstrated in pediatric and adolescent patients from Germany (Table 1). Three pediatric patients with severe hemophilia A who were previously treated with recombinant FVIII (rFVIII) and wanted improved bleed protection with the same regimen. After switching to rVIII-SingleChain, all three patients showed a good outcome with no incidence of inhibitor development. One patient had a history of poor adherence to a prophylactic regimen with pdFVIII (1000 IU 3×/week) and switched to rVIII-SingleChain (1000 IU 3×/week). The patient did not have a history of joint bleeds, however, to guarantee higher trough levels and prevent any joint damage from occurring in the future they were switched to the same regimen with rVIII-SingleChain (1000 IU 3×/week, 23 kg)⁵. The potential for micro bleeds was another reason for the interest in improved protection. After the switch to rVIII-SingleChain, this patient showed good outcomes and improved compliance to treatment. The patient underwent two tooth extraction surgeries, one with their previous rFVIII product and one with rVIII-SingleChain. The surgery covered by rFVIII was managed with a bolus infusion of 2000 IU (70 IU/kg); the following morning the FVIII trough level was 51% and an additional dose of 1000 IU (35 IU/kg) was administered. The surgery with rVIII-SingleChain was covered by a reduced consumption of FVIII but with comparable trough levels; a bolus dose of 1500 IU (35 IU/kg) with no additional infusions achieved a trough level of 54% (calculated with the one-stage assay and a conversion factor of 2)¹⁵.

Clinical experience from a French Hemophilia Treatment Center has also highlighted the possibility of modifying treatment regimens using PK-guided prophylaxis to reduce the treatment burden (Table 1). In three patients with severe hemophilia A who switched to rVIII-SingleChain, including two adult cases and one adolescent case, all patients received fewer infusions with rVIII-SingleChain compared to their previous product. The use of PK measurements to guide treatment management is particularly useful for pediatric/adolescent patients with active lifestyles and a history of frequent traumatic bleeds. For example, a 15-year-old patient with severe hemophilia A who played regular sports (swimming, badminton) had a history of rare spontaneous bleeds but frequent traumatic bleeds and a target joint (right elbow). The patient was previously treated with rFVIII (1500 IU, 3×/week) and obtained an FVIII trough level of 3.1% after 48 h and a half-life of 11.1 h. The patient was adherent to this regimen but still experienced breakthrough bleeds (ABR of 4–5). The patient wanted to have better bleed protection to be more physically active and was switched to rVIII-SingleChain (1500 IU, 3×/week); this regimen provided an FVIII trough level of 10.2% after 48 h and a half-life of 17.2 h. Five months after switching, the ABR was reduced to 1, and both the patient and his parents reported feeling more confident due to the improved bleed protection afforded by rVIII-SingleChain. The patient also reported more physical and social fulfillment and has begun two additional sporting activities (table tennis and volleyball). Due to the success of switching, the patient was able to reduce his treatment frequency and consumption by adopting a regimen of 2000 IU, 2×/week.

As shown in the above cases, switching to rVIII-SingleChain can allow patients to individualize their treatment to reduce their infusion frequency, and this can increase adherence (Table 1). Higher FVIII trough levels are likely to be maintained, increasing protection against joint bleeds and safeguarding long-term joint health⁵. Five patients from Germany with a history of severe arthropathy and poor adherence to their previous prophylaxis regimen reported a positive impact of switching to rVIII-SingleChain. Three patients were able to reduce the number of infusions and two patients were able to maintain their previous dosing regimen, but with improved bleed protection due to the improved trough level of rVIII-SingleChain compared to their previous product. One patient was a 60-year-old gentleman with a history of poor venous access and multiple arthropathies who was previously treated with rFVIII (2000 IU every 2 days, 100 IU/kg/week). The patient achieved a 3-day FVIII trough level of 2.4% (measured with the one-stage assay) with a 2000 IU dose of rFVIII. He showed poor adherence to this regimen and regularly infused under half the recommended dose (2000 IU 2×/week, 54 IU/kg/week). He was originally switched to a long-acting factor product (3000 IU 2×/week, 80 IU/kg) but experienced an allergic reaction. The patient then switched to rVIII-SingleChain prophylaxis (3000 IU 2×/week, 81 IU/kg) and has experienced no relevant bleeds. The patient’s PK levels improved with rVIII‑SingleChain; the 3-day FVIII trough level was 6.7% (measured with the one-stage assay) with a 3000 IU dose of rVIII‑SingleChain. The patient also underwent surgery with lower consumption and higher factor activity compared to surgery under the previous rFVIII treatment.

The clinical experience from a single center in Italy describes the efficacy and tolerability of rVIII‑SingleChain in one patient previously treated episodically, and also in two previously untreated patients who were part of the AFFINITY clinical trial extension study (Table 1). Clinical experience from an Italian center highlighted four patient cases with severe hemophilia A, including three pediatric patients and one adult; two of the pediatric patients were previously untreated patients (PUPs) and the adult case had only previously received episodic treatment. After switching to rVIII-SingleChain, one of the pediatric patients and the adult patient were successfully treated with no inhibitor development. In the remaining two pediatric cases, one patient developed a low-titer inhibitor and one developed a high-titer inhibitor, both were successfully treated with immune tolerance induction using rVIII-SingleChain. Both patients continued their prophylaxis regimens, and neither patient experienced joint bleeds since the start of prophylaxis. One of the pediatric PUPs (2 years old) began prophylaxis with rVIII-SingleChain (35 IU/kg, 2×/week) as part of the PUPs study in the AFFINITY clinical trial program. After twelve exposure days, the patient developed a high-titer inhibitor and underwent successful immune tolerance induction therapy with rVIII-SingleChain (50 IU/kg, 3×/week). Tolerance was achieved after 15 months, and the patient continued on a prophylaxis regimen with 40 IU/kg 3×/week.

Alongside factor replacement concentrates, non-factor replacement therapies, including emicizumab, are being developed to address the unmet needs in patients with hemophilia A¹⁶. Emicizumab is a recombinant, humanized bispecific monoclonal antibody that binds FIXa and FX and substitutes for activated factor VIIIa^17,18. The long half-life of emicizumab allows for sustained protection from breakthrough bleeds, without peaks or troughs in FVIII levels^16,18. Emicizumab has demonstrated efficacy with low spontaneous bleed rates, low joint bleed rates, and improved quality of life ratings and is approved for subcutaneous administration up to once a month^16–18. The limitations of emicizumab, especially in patients with high physical activity or those undergoing surgery, are that breakthrough bleeding may occur and could require FVIII replacement therapy for treatment. A further limitation is that there are limited options for individualizing emicizumab treatment.

In summary, all patients are potentially suitable for switching to rVIII-SingleChain, particularly those who did not respond well to alternative products. The PK profile of rVIII-SingleChain affords clinicians the freedom to tailor prophylaxis to the patient’s needs^7,13. Maintaining the same dosing regimen can allow greater physical activity or enhanced bleed protection while reducing the dosing frequency can lower the treatment burden and improve adherence. The clinical experience outlined above is consistent with other real-world experiences with rVIII-SingleChain^19–21. Finally, the advent of non-factor replacement therapies offers potential alternatives for the management of hemophilia A; however, there is still a need for factor replacement with FVIII. This report outlines selected clinical cases presented during the 3rd Alliance for Coagulation Academy Virtual Meeting, focusing on clinical experience with rVIII‑SingleChain, rIX-FP, and emicizumab. Other long-acting FVIII products are available which allow similar dosing regimens to rVIII-SingleChain^22,23, but discussion of clinical cases with these products is beyond the scope of this report.

One interesting observation is that the FVIII trough levels reported in the clinical experiences described above for rVIII-SingleChain are higher than those reported in the AFFINITY clinical trial program. A population PK model of rVIII-SingleChain in adult patients with severe hemophilia A reported a median (IQR) FVIII trough of 1.9 (0.58–8.0) IU/kg for 2×/week dosing with 50 IU/kg and 4.4 (1.1–17.3) for 3×/week dosing with 50 IU/kg²⁴. In comparison, PK analyses from a single French Hemophilia Treatment Center reported a median (IQR) 48 h FVIII trough of 9.8 (8.8–11.3) from five patients with a median dose of 48 IU/kg 3×/week.

Clinical experiences of switching patients with hemophilia B to prophylaxis with rIX-FP

rIX-FP (albutrepenonacog alfa, IDELVION^®, CSL Behring) is a recombinant fusion protein that links recombinant FIX (rFIX) with recombinant human albumin. Linking to albumin extends the half-life of rFIX to ∼90–105 h^8,25–27. rIX-FP has demonstrated improved PK and PD with a considerably longer half-life than standard-acting rFIX and pdFIX products in preclinical and clinical studies; often exceeding the minimum trough levels of 3–5% recommended by WFH guidelines^1,8,27–30. rIX-FP is approved for the treatment and prophylaxis of bleeding in adult/adolescent and pediatric patients with hemophilia B at dose intervals of 7 days; dose intervals of up to 14 days can be adopted in adult/adolescent patients whose disease is well-controlled^31,32. Extended dosing regimens with rIX-FP up to 21 days were approved by the European Medicines Agency in 2020 for selected patients ≥18 years, provided they are well-controlled on a 14-day rIX-FP dosing interval³¹.

Patients switching to rIX-FP from a previous standard-acting product can achieve higher trough levels, improved bleed protection, and a reduced treatment burden (Table 2). Clinical experience in Germany reported two adult patients and one pediatric case with severe hemophilia B who wished to maintain efficient bleed protection but with a lower treatment burden. After switching to rIX-FP, all three cases achieved higher FIX trough levels compared with their previous prophylaxis regimen. All patients were also able to be more physically active and have greater confidence in participating in physical activities. One example of this was a 21-year-old patient with severe hemophilia B and history of intracerebral bleeds. The patient was previously treated with rFIX (2000 IU 3×/week), which provided a FIX trough level of 2% after 72 h. He had a sedentary lifestyle and no history of spontaneous bleeds or joint bleeds; however, he had experienced two traumatic bleeds in the six months before switching. The patient wanted a lower treatment burden but to keep the same level of bleed protection. After his last intracerebral bleed in 2017, the patient was switched to rIX-FP (4000 IU every 10 days) following a PK evaluation. This regimen provided a FIX trough level of 10% after 10 days and a half-life of 140 h estimated with WAPPS-Hemo¹⁴. The patient continued to have excellent bleed control with no spontaneous bleeds, joint bleeds, or intracerebral bleeds after switching. The patient could also begin playing table tennis twice a week without further bleeding.

Clinical experience from Italy demonstrated that tailoring prophylaxis with rIX-FP to reduce the treatment burden is important for pediatric and elderly patients alike (Table 2). One example was a pediatric case (6 years old) with severe hemophilia B previously receiving prophylaxis with a standard-acting product (40 IU/kg 2×/week). Due to recurrent breakthrough bleeds at the end of the dosing interval, the patient switched to rIX-FP (50 IU/kg 1×/week). This resulted in a reduced bleeding frequency, including traumatic bleeds, and the patient has been able to play basketball twice a week. Reducing the treatment burden is also important for elderly patients who wish to maintain a low treatment burden and have a phobia of needles. For example, an adult case (71 years old) was treated episodically with pdFIX throughout his life due to a fear of injections. The patient underwent vascular surgery with his usual pdFIX concentrate but subsequently began prophylaxis with rIX-FP in the post-operative period (50 IU/kg every 10 days, based on the observed PK profile). The treatment was modified to 40 IU/kg 1×/week for the patient’s convenience, with a reported FIX trough level of 10%.

Clinical experience from Israel also demonstrated a positive experience of tailoring the dose and dosing interval to the patient's needs (Table 2). An example of this is an adolescent case (16 years old) with severe hemophilia B who was previously treated with a pdFIX product (40 IU/kg, 2×/week) and had a history of breakthrough bleeding (ABR of 11) and target joints in the elbow and knee, indicating a need to improve their treatment. The patient switched to a higher dose and shorter dosing regimen with rIX-FP (75 IU/kg every 10 days). Following this switch, the patient has been able to begin high-risk work as a window cleaner and regularly attends the gym. Despite this high activity level, following the switch to rIX-FP the patient’s bleeding rate reduced from an ABR of 11 to 4; the target joint in the knee also resolved.

Switching to long-acting FIX products has broader implications for patients beyond improved bleed control; clinical experience from Switzerland has demonstrated the impact on quality of life after switching to rIX-FP (Table 2). One adult patient (43 years old) with severe hemophilia B and a history of episodic treatment with a pdFIX product experienced many breakthrough bleeds, with an ABR of 25. The patient had severe arthropathy in his ankles, elbows, and knees, resulting in physical disability and an inability to walk 200 m or work because of the pain. Due to these limitations on the quality of life, the patient agreed to begin prophylaxis with rIX-FP (50 IU/kg, every 14 days). This regimen was based on the results of a population-based PK model. During follow-up, the patient’s synovitis improved and the ABR was reduced from 25 to 3, with all three bleeds resulting from trauma. The patient remained adherent to the treatment and reported improvements in his quality of life. This case highlights the benefits of beginning prophylaxis, even in patients previously treated with long-term episodic treatment.

To summarize the clinical experience of switching patients with hemophilia B to prophylaxis with rIX-FP, extended dosing intervals are potentially beneficial in a wide variety of age ranges and situations, including surgery. Patients with high activity levels, especially children, may benefit from extended dosing intervals. rIX-FP may be a useful treatment option in elderly patients who wish for a high level of protection from bleeding as well as a low treatment burden. The clinical experiences reported here are consistent with the clinical trial results of rIX-FP and other reports of real-world experience with rIX-FP. rIX-FP enables higher FIX troughs than those recommended by the WFH; the majority of patients can maintain FIX activity >5%, which is consistent with a mild bleeding phenotype.

Limitations

This report provides a summary of clinical experiences of switching patients to rVIII-SingleChain or rIX-FP. These selected patient cases were originally presented at the 3rd Alliance for Coagulation Academy Virtual Meeting, and are summarized in this report to provide an additional published record of these cases. The data presented here are consistent with the clinical trial data and real-world evidence for rVIII-SingleChain^7,13,19–21 and rIX-FP^8,30,33–35. Despite this, this report is limited by the number of patients presented.

Future studies should also look to report the effects of switching to different factor replacement products. Whilst detailed discussion on the role of non-factor replacement products was beyond the scope of this report, it should be acknowledged that these products are also a treatment option for patients with hemophilia.

Conclusions

rVIII-SingleChain and rIX-FP are useful medications in hemophilia treatment to reduce the treatment burden in a wide range of patients, from pediatric to elderly patients. This is driven by their improved PK profile compared with standard-acting products. It is important to take into consideration all of the relevant information, including the physical and social fulfillment of the patient, when deciding to switch to rVIII‑SingleChain or rIX-FP. rVIII-SingleChain and rIX-FP also allow treatment to be individualized according to patients’ expectations; the individualization of treatment can improve patient adherence and provide fewer constraints on physical activity imposed by hemophilia. The physician plays an important role in the motivation of patients as they understand not only the patient's needs but also the potential benefits of the new treatment. Patients may wish to switch factor products for a variety of reasons; therefore, it is crucial for physicians to have empathy and to understand why patients switch and what they expect from switching.

Transparency

Declaration of funding

The patient cases presented in this report were originally presented at the 3rd Alliance for Coagulation Academy Virtual Meeting (29–30 October 2020); this meeting was sponsored by CSL Behring. Medical writing support for this report was funded by CSL Behring.

Declaration of financial/other relationships

JO has received reimbursement for attending symposia/congresses, honoraria for speaking and/or consulting, and funds for research from Bayer, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and Swedish Orphan Biovitrum. SWP has received consulting fees from Apcintex, ASC Therapeutics, Bayer, Biomarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, Roche/Genentech, Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure. MEM has acted as paid consultant/advisor/speaker for Bayer Healthcare, Biomarin, CSL Behring, Catalyst Biosciences, Grifols, Kedrion, Novo Nordisk, Pfizer, Sobi, Roche, Spark Therapeutics, Takeda, Octapharma, LFB, Sanofi, and UniQure. RK has received reimbursement for attending symposia/congresses, honoraria for speaking and/or consulting, and funds for research from Bayer, Biomarin, Biotest, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Takeda/Shire, Swedish Orphan Biovitrum and uniQure. AH has received reimbursement for attending symposia/congresses, honoraria for speaking and/or consulting, and funds for research from Bayer, CSL Behring, Novo Nordisk, Octapharma, LFB, Pfizer, Roche, Takeda/Shire, and Swedish Orphan Biovitrum. MO reports grants and honoraria for speaking and/or consulting from Bayer, Biotest, Takeda, CSL Behring, Octapharma, Pfizer, Roche, Sobi, and NovoNordisk. GG has undertaken speaker duties for Bayer, Shire, Pfizer, CSL Behring, Novo Nordisk, Sobi, Biotest, Nordic, and Octapharma, and has acted as a consultant for Bayer, Shire, Pfizer, CSL Behring, Novo Nordisk, Sobi, BPL and Octapharma, and has received research funding from Bayer, Shire, Pfizer, CSL Behring, Novo Nordisk, and Sobi. GK received research grant support from Alnylam, BPL, Bayer, Baxalta, CSL Behring, Opko biologics, Pfizer, Shire; consultant for Alnylam, Bayer, Opko biologics, Pfizer, Shire, Roche; honoraria/speakers bureau for Bayer, CSL, Pfizer, Roche. WM Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, Takeda/Shire, uniQure. JS is an employee of CSL Behring. IH reports advisory and consultancy fees from Bayer, CSL Behring, NovoNordisk, Octapharma, Pfizer, Roche, Shire/Takeda, Sobi, Uniqure; multisponsoring of a hemophilia nurse HCCC by Bayer, Biotest, CSL Behring, NovoNordisk, Octapharma, Pfizer, Shire/Takeda, Sobi and travel grants from Bayer, Biotest, CSL Behring, NovoNordisk, Octapharma, Pfizer, Shire/Takeda, Sobi.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

JO, SWP, MEM, RK, AH, MO, GG, GK, WM, JS, and IH were involved in drafting the paper and revision of the paper. JO, SWP, MEM, RK, AH, MO, GG, GK, WM, JS, and IH approved the final version for publication.

Acknowledgements

The medical writing support was provided by Meridian HealthComms, Plumley, UK in accordance with good publication practice (GPP3) and funded by CSL Behring.