These are exciting times for the hemophilia community: over the last decade the management and lives of patients are being actually transformed by the introduction in the clinical practice of innovative products, also providing newer therapeutic approaches additional to conventional replacement of the deficient factors (i.e., nonreplacement products and gene therapy).[1] Innovative approaches, including the first introduced nonreplacement product, emicizumab, are being also experienced and investigated in the treatment of bleeding disorders other than congenital hemophilia. For these reasons, this latest Issue of Seminars in Thrombosis and Hemostasis is dedicated not only to the current advances and perspectives in the management of hemophilia A (HA) and B (HB), but also in other challenging conditions with unmet treatment needs, like acquired hemophilia, von Willebrand disease (VWD), and hereditary hemorrhagic telangiectasia (HHT).
Introducing this evolving scenario, the first of the 11 chapters of the current issue reviews the outstanding progress of therapeutic products for hemophilia over the last half a century, from the plasma-derived replacement products, through the era of recombinant technologies—standard half-life and extended half-life (EHL) factor concentrates—up to the recent nonreplacement approaches and the first licensed gene therapy products.[2] In parallel, the management of persons with hemophilia (PWH) has also evolved: personalized prophylaxis regimens became the standard of care and the bar of therapeutic target continuously raised from the prevention of bleeding to the avoidance of joint damage and the best possible quality of life. Currently, the unimaginable perspective of “health equity,”[3] i.e., leading a healthy life without physical and psychological restrictions, similar to nonaffected peers, is becoming achievable, thanks to therapeutic products able to virtually normalize hemostasis.[2]
The achievements, open issues, and perspectives of the different therapeutic approaches currently available for hemophilia are expanded in the subsequent chapters. Regarding replacement products for HA, the literature data showing the benefits of EHL Factor (F) VIII products in improving prophylaxis feasibility, individualization, and outcomes are summarized by Mancuso.[4] These modified FVIII EHL molecules (by Fc-fusion or pegylation) introduced in the last decade have enabled tailored prophylaxis regimens according to the specific protection and convenience needs, with reduced infusion frequency and/or higher FVIII trough levels. A remarkable improvement of pharmacokinetic properties is shown by the new-generation molecule efanesoctocog alfa, able to overcome the binding to the endogenous von Willebrand factor (VWF), at variance with previous products, and to provide FVIII levels and hemostatic protection in the nonhemophilia range over much longer time periods. Mancuso also discusses these recent achievements,[4] claiming the renaissance of FVIII replacement treatment[5] against the change of paradigm introduced by emicizumab, the first nonreplacement agent for prophylaxis in hemophilia. Indeed, this FVIII mimetic, which revolutionized the management of PWH A with inhibitors, making possible a highly effective prophylaxis of bleeding, provided an alternative even for those without inhibitors, with a lower treatment burden thanks to the long-interval subcutaneous administration.
The advance and potential implications of nonreplacement products are discussed by Jiménez-Yuste in the next chapter.[6] Beyond emicizumab, newer FVIII mimetics (mim8, NXT007) and several rebalancing agents, enhancing thrombin generation by inhibiting the natural anticoagulant pathways, are in different phase of clinical trials or being introduced in the market. The latter, including two antitissue factor pathway inhibitor monoclonal antibodies (concizumab and marstacimab), an antithrombin small interfering RNA (fitusiran) and agents targeting the activated protein C (like serpinPC) or protein S, are effective in both HA and HB, regardless of inhibitors. Therefore, these products provide a prophylactic approach particularly useful for the challenging management of patients with HB and inhibitors.[7] Nonreplacement products, unlike the intravenous peak-and-trough hemostatic replacement by factor concentrates, generate stable thrombin levels by subcutaneous administration, shifting severe hemophilia toward a milder phenotype. These clear advantages should be considered together with still open issues, including the potential thrombotic risk requiring mitigation measures (particularly the optimization of combined replacement/bypassing treatment for surgery or intercurrent bleeding), the development of anti-drug antibodies (ADA) and the absence of standardized laboratory assessments.[6]
Three chapters then deal with the most innovative approach of gene therapy in hemophilia.[8]
[9]
[10] Almost four decades of preclinical and clinical trials have led to the development of adeno-associated viral (AAV) vector mediated gene transfer for endogenous production of FVIII and FIX in HA and HB, respectively. Bala and Thornburg review the results and challenges of gene therapy trials in HA, leading to the approval by regulatory authorities of the first gene therapy product, valoctocogene roxaparvovec.[8] While bleeding rates and use of factor replacement therapy significantly improved after this one-shot treatment, sustainability, and duration of response show wide individual variability, with overall decline in FVIII expression over time. However, this reduction is more relevant in the first 2 years, FVIII levels tending to stabilize later, as shown from the recently published data up to 7 years of the phase 1 to 2 studies and the 3-year outcomes of the phase 3 trial.[11]
[12] The major concerns are related to the possible liver toxicity (aminotransferases increase in high proportion of patients) requiring immunosuppression and the need for long-term safety data. The authors remark that real-life applicability of gene therapy for HA requires appropriate patient screening, infrastructure setup, careful monitoring including data collection of patient-reported outcomes, and innovative payment schemes.[8]
The same technology (AAV vector gene transfer) and challenges (sustained and durable expression) were confronted in the development pathway of gene therapy for HB, reviewed by Castaman and Miesbach.[9] The recent trials using the natural occurring FIX Padua, which allows for a 5- to 8-fold higher activity of factor IX, to enhance the level of transgene expression, showed good results and accumulating data suggest that long-term expression could be maintained at a significant hemostatic level. Three-year outcomes after gene therapy with etranacogene dezaparvovec[13] and 15-month follow-up after fidanacogene elaparvovec[14] consistently confirm the potential to provide long-term benefits with sustained factor activity levels predicted to last several years in the majority of patients. However, concerns on liver enzymes elevation, although reported in lower proportion of patients than in those receiving HA gene therapy, and on long-term safety remain and should be addressed with careful and prolonged multidisciplinary follow-up of treated patients.
The patient perspectives on burden of disease and about knowledge, expectations, and concerns on gene therapy have been investigated by a multidisciplinary panel through a survey among Italian hemophilia patients and caregivers reported in the chapter by Mansueto and colleagues.[10] The results highlight that, despite current treatments, about half of patients experience not negligible numbers of bleeding and report pain and/or joint function limitations, high treatment burden, concerns about management of breakthrough bleeding, and anxiety/fear for its occurrence. Most participants know of gene therapy and expect improvements in their clinical outcomes and quality of life, but they are unaware about some aspects, including the once-off dosage and the permanent cure currently not achievable. Concerns are focused more on efficacy issues than safety. Educational initiatives are needed and requested by patients, as well the support of a multidisciplinary team before, at the time and over the monitoring of this “transformative” therapy.[10]
Therapeutic advances in the management of hemophilia have been largely focused on severe disease, as persons with nonsevere hemophilia (PWNSH) have not been included in many clinical trials and marketing authorizations refer to the investigated patients. Moreover, innovative replacement therapies are currently targeting factor levels that are above those of a large proportion of PWNSH. Overall, therapeutic advances are providing/expected to provide better clinical outcomes in severe hemophilia than those actually experienced in many PWNSH. These relevant issues are discussed by Dolan et al,[15] who also remark that perceptions about a “nonsevere” phenotype contributed to fewer research initiatives, fewer guidelines on optimal management, and a lack of standards for surveillance for PWNSH. The authors timely review many aspects about nonsevere hemophilia that require clinical and research attention, from the disease awareness and detection, the bleeding phenotype, risk and complications (focusing on intracranial hemorrhage and joint disease), to the different settings of treatment, including the role for prophylaxis, management of surgery, inhibitor patients, and the neglected population of affected women.[15] This renewed and in-depth interest is crucial to ensure the “health equity” in care for all PWH.
The achievements of therapeutic innovations in congenital hemophilia could be extrapolated in the management of other bleeding disorders. The enhancement of thrombin generation by nonreplacement agents is potentially useful in other factor deficiencies[16] and the FVIII-mimetic effects of emicizumab are being investigated in clinical settings in which FVIII deficiency plays a major role, like acquired hemophilia A (AHA) and severe VWD. Franchini and Focosi review the use of emicizumab in AHA patients as a strategy for treating and, in particular, preventing severe recurrent bleeding, as suggested by many case reports/series and two recent clinical trials. This approach is promising in reducing mortality and morbidity in this setting, together with the optimization of immunosuppressive strategies, in which the role of rituximab is increasingly recognized. These two drugs, currently used “off-label” in AHA, may contribute to improve efficacy and safety of its challenging management.[17]
Emicizumab, again, has been considered as a potential prophylaxis approach for patients with type 3 VWD, who show FVIII levels in the range of moderate hemophilia, particularly for those developing alloantibodies against VWF. This condition is rare, but potentially life-threatening, not only for difficult-to-treat bleeding, but also for the risk of anaphylactic reactions. Giuffrida et al report the complex management of a type 3 VWD woman who developed anti-VWF alloantibodies and severe anaphylaxis, now successfully receiving an off-label prophylaxis regimen with emicizumab for more than 3 years. Further 10 recently published cases are reviewed.[18] These clinical experiences, although in a small number of patients, support the efficacy and safety of emicizumab in patients with type 3 VWD with and without inhibitors requiring prophylaxis because of a bleeding phenotype similar to that of hemophilia.
Challenges in VWD patients also include the diagnostic approach. The recent international guidelines[19] pointed out many aspects, including the use of Bleeding Assessment Tools (BAT) and assays for platelet-dependent VWF activity (PD-VWFact) and the role for other laboratory tests, the search for VWF gene variants and the desmopressin (DDAVP) trial. Federici discusses the impact of these guidelines into clinical and laboratory practice reporting the results of a survey carried out among Italian specialists managing VWD patients. BAT, VWF antigen, and FVIII activity measurements are currently used in all centers, PD-VWFact assays and DDAVP infusion test in >80% of cases, but other tests are less widely available. Based on this information, a simplified diagnostic algorithm using the BAT and a few automated tests before and after DDAVP has been proposed. This approach will be validated prospectively at Italian specialist centers.[20]
The last chapter of the Issue is dedicated to the HHT, an inherited vascular disorder characterized by abnormal blood vessels (telangiectasias as well arteriovenous malformations [AVMs]) that can form in various districts and lead to mild to life-threatening bleeding episodes, depending on the severity and location of vascular abnormalities. Cerrone et al, after summarizing genetic, pathophysiological, and clinical features of HHT, review the interesting perspectives in treatment of this challenging disease, still based on nonspecific approaches.[21] Recent clinical trials provide promising results using several drugs with different antiangiogenic properties, including bevacizumab, pazopanib, tacrolimus, and the immunomodulatory imides thalidomide and pomalidomide. The era of HHT-specific treatments seems about to start, however, limitations in terms of efficacy, side effects, and amount of available data as well uncertainties whether the effects of these drugs can be extended to large AVMs, require larger, well-designed trials to validate their efficacy and safety.[21]
While wishing all our readership enjoyable reading and inspiring insights, we warmly thank all the authors who provided such excellent contributions, able to reflect the valuable achievements and the enthusiastic perspectives currently shared by patients, clinicians, and researchers.
