Predicting joint involvement through tailored prophylaxis in severe haemophilia A, is it possible?

INTRODUCTION: Tailored prophylaxis is the current treatment regimen for patients with severe haemophilia A. Recently, published guidelines describe two possible approaches, based on clinical characteristics or estimation of pharmacokinetic parameters. However, both have strengths and weaknesses, and their characteristics need to be integrated to optimize treatment appropriately. In this paper, we present a model that considers together the characteristics of prophylaxis and the relevance of each. METHODS: The age at initiation of prophylaxis, number of bleeding events, treatment regimen, therapeutic adherence, FVIII trough levels, and joint status were analyzed in 59 patients followed at La Paz University Hospital between January 2000 and December 2019. RESULTS: The mean duration of primary prophylaxis of 113.37 ± 57.79 months. Eighty-three percent (n = 49) had no joint status involvement at the end of follow-up (HJHS and HEAD-US = 0). The median ABR was 0.7 (IQR 0.2 -1.0) and 54.2% presented trough levels of FVIII during follow-up >1 IU/dL. 72,9% engaged in some type of physical activity and overall adherence was over 85% in all patients evaluated. The regression analysis performed, considering all these factors, showed that the initiation of prophylaxis before 21 months of age was the most relevant protective factor against the appearance of joint involvement (OR 88.33 p.031 CI 95% 1.49-5224.40) CONCLUSION: Early initiation of prophylaxis was the most relevant factor in the protection of joint status. More comprehensive analysis models adapted to the characteristics of each population, are needed to adequately individualize treatment.

Long-term outcomes with emicizumab in hemophilia A without inhibitors: results from the HAVEN 3 and 4 studies.

Background: Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX and FX, mimicking the function of missing or deficient activated FVIII in people with hemophilia A (HA). Objectives: To evaluate the long-term efficacy and safety of emicizumab prophylaxis in people with HA without FVIII inhibitors in the HAVEN 3 and 4 studies. Methods: HAVEN 3 and 4 were phase 3 open-label studies. Participants received emicizumab maintenance doses of 1.5 mg/kg every week or 3 mg/kg every 2 weeks (HAVEN 3), or 6 mg/kg every 4 weeks (HAVEN 4). Long-term efficacy and safety were assessed. Results: A total of 151 and 40 individuals without FVIII inhibitors received emicizumab in HAVEN 3 and 4, respectively. At the last patient, last visit dates (May 12, 2022 [HAVEN 3] and June 29, 2022 [HAVEN 4]), the median (range) duration of emicizumab exposure across the 2 studies was 248.1 (6.1-287.1) weeks. The mean (95% CI) annualized bleed rate for treated bleeds was 2.0 (0.23-7.15) for weeks 1 to 24, decreasing to 0.9 (0.01-5.28) by weeks 217 to 240. Overall, 188 (98.4%) participants experienced ≥1 adverse event (AE), with 185 treatment-related AEs in 71 (37.2%) participants. Forty-four (23.0%) participants reported a serious AE. Two thromboembolic events were reported, which were deemed unrelated to emicizumab by the investigator. No thrombotic microangiopathies were reported. Conclusion: With nearly 5 years of emicizumab exposure across the HAVEN 3 and 4 studies in people with HA without inhibitors, these data indicate continued bleed control with no new safety signals observed during long-term follow-up.

Management of Urgent Bleeding in Patients with Hemophilia A: Focus on the Use of Emicizumab.

Management of patients with hemophilia A (HA) requires the knowledge and experience of specialized health care professionals. However, these patients may need to be attended in emergencies, outside the referral hospital, where health care professionals do not know about hemophilia and/or new innovative treatments. This study aimed to develop a simple and practical algorithm that could be used in emergency situations by nonspecialized treaters in HA and bleeding with or without factor VIII (FVIII) inhibitors under emicizumab prophylaxis. A group of experts agreed on a simple algorithm, easy to operate, adapted from previous international guidelines, and based on their clinical experience. The proposed algorithm starts with identifying the patient, confirming the diagnosis of HA, prophylaxis with emicizumab, and/or use of other treatments. After stabilizing the patient and stratifying the bleeding risk, the patient is managed according to the presence/absence of FVIII inhibitors. Patients without FVIII inhibitors should receive FVIII concentrate. Dose and follow-up depend on bleeding localization and severity. Patients with FVIII inhibitors should preferably receive recombinant activated factor VII as bypass agent. A basic coagulation assay, FVIII assessment, and FVIII inhibitors detection assays are necessary in an emergency. However, these tests should be interpreted with caution and appropriately chosen, as emicizumab may alter the results. The management of patients with HA is challenging in emergency situations, especially if they are treated with new agents. Nonspecialized in coagulopathies health care professionals have limited understanding of the disease, highlighting the need for an algorithm to assist them in making informed decisions.

Knee replacement surgery in a patient with acquired von Willebrand disease: a case study with recommendations for patient management.

Introduction and importance: Acquired von Willebrand disease (AvWD) is a rare underdiagnosed bleeding disorder caused by alterations in the levels of the major blood-clotting protein von Willebrand factor (vWF). The clinical and laboratory parameters of AvWD are similar to congenital vWD, but it is found in individuals with no positive family history with no underlying genetic basis. The disease remains multifactorial and incompletely understood. Proposed mechanisms include the development of autoantibodies to vWF, absorption of high molecular weight vWF multimers that impair normal function, shear stress induced vWF cleavage and increased proteolysis.The aetiology of the disease is variable, the most common being hematoproliferation, lymophoproliferation, myeloproliferation and autoimmune and cardiovascular disorders. Consensus and protocols for AvWD patients that require major surgery are currently lacking. Patients with AvWD can experience thrombotic events during surgery as a result of therapeutic interactions with pro-thrombotic risk factors. Case presentation: Here, the authors report a patient with AvWD requiring a knee prosthesis implantation due to chronic pain, limited range of motion and functional impairment. The patient had a high risk of bleeding during surgery and was at risk of thrombosis due to age and obesity. Clinical discussion: Perioperative care required a collaborative approach and the management of bleeding. The patient was administered vWF concentrate Willfact lacking Factor VIII to prevent haemorrhage and to minimize the risk of thrombosis. Conclusion: The treatment was effective and well-tolerated. The authors use this information to provide recommendations for AvWD patients for whom major surgery is indicated.

Outcomes and outcome measures.

INTRODUCTION: Advances in haemophilia treatment have resulted in a near-normal life expectancy, lower burden of bleeding and treatment, and improved quality of life in high-income countries. Bleeding rate is approaching zero and novel parameters should be evaluated to assess the efficacy of treatment not only from the clinical point of view by using new methodologies (e.g. joint health assessment), but also from the patient's perspective (e.g. pain, quality of life, treatment satisfaction). METHODS AND RESULTS: This approach should be aimed at combining objective clinical methodologies and patient-reported outcomes (PROs). However, some instruments used for assessing PROs are still suboptimal and not properly validated. Recent evidence suggests that these tools can take advantage from a more personalized designed approach and could be effectively improved and serve to facilitate the patient's self-evaluation. For other congenital bleeding disorders (BDs), a set of patient-relevant outcomes has been also defined that overlap substantially those of haemophilia, including bleeding, side effects and complications, and PROs, such as pain, physical functioning, impact on daily life including school and work and mental health. There is a growing focus on addressing women-specific outcomes in BDs, reflecting an increased awareness of the unique challenges faced by women in this context. However, the development of tailored tools is imperative to further advance the progress in managing women with BDs, ensuring more accurate monitoring and personalized care. CONCLUSIONS: How incorporating these outcome measures in the process of approval of novel treatments for these disorders by regulatory authorities remains to be established.

Arthroscopic ankle surgery in people with haemophilia.

INTRODUCTION: People with haemophilia (PWH) not administered primary haematological prophylaxis since childhood, that is, those treated haematologically on demand or not treated at all, often experience the degeneration of the ankles, leading to pain and functional impairment. AIM: To analyse the outcomes and complications of arthroscopic ankle surgery performed on PWH. METHODS: For this narrative review of the literature, a search was conducted in PubMed on 2, December 2023, using the keywords "haemophilia", "ankle" and "arthroscopy". Of the 29 articles identified, 15 specifically related to ankle arthroscopy in PWH were selected (inclusion criterion). The remaining articles did not meet this requirement (exclusion criterion) and were therefore eliminated. RESULTS: Arthroscopic procedures (arthroscopic synovectomy, debridement and arthrodesis of the ankle) are increasingly used in the surgical treatment of haemophilic ankle arthropathy. Although arthroscopic ankle surgery offers good outcomes in patients with haemophilia, the procedure is not free of complications, which range from 7.9% for arthroscopic ankle debridement to 13.1% in arthroscopic ankle synovectomy and 17.8% in arthroscopic ankle arthrodesis, respectively. The non-union rate of arthroscopic ankle arthrodesis is 7.1% (2/28). CONCLUSION: Although arthroscopic interventions in the haemophilic ankle (synovectomy, debridement, arthrodesis) offer good functional outcomes, they are associated with a non-negligible rate of complications. Arthroscopic ankle surgery in PWH is major surgery and should be treated as such.

Eptacog beta for the management of patients with haemophilia A and B with inhibitors: A European perspective.

Eptacog beta (activated), a recombinant human factor VIIa (rFVIIa), was approved by the US Food and Drug Administration (FDA) in 2020 (SEVENFACT®, LFB & HEMA Biologics) and the European Medicines Agency (EMA) in 2022 (CEVENFACTA®, LFB). In Europe, eptacog beta is indicated for the treatment of bleeds and the prevention of bleeds during surgery or invasive procedures in adults and adolescents (≥12 years old) with congenital haemophilia A or B with high-titre inhibitors (≥5 BU) or with low-titre inhibitors who are expected to have a high anamnestic response to factor VIII or factor IX, or to be refractory to increased dosing of these factors. The efficacy and safety of eptacog beta were evaluated in three Phase III clinical studies, PERSEPT 1, 2 and 3. For the EMA filing dossier, the analysis of data from PERSEPT 1 and 2 differed from the analysis used to support the filing in the US. In this review, we summarise current data regarding the mode of action, clinical efficacy and safety of eptacog beta for the management of haemophilia A and B in patients with inhibitors from a European perspective. In addition to providing a valuable summary of the analyses of the clinical data for eptacog beta conducted for the EMA, our review summarises the potential differentiators for eptacog beta compared with other current bypassing agents.

A post hoc comparative real-world analysis of HEAD-US score for joint health assessment of patients with severe haemophilia A and B in Spain.

AIM: Joint damage due to haemarthrosis can be effectively monitored with point-of care ultrasound using the Haemophilia Early Arthropathy Detection with US (HEAD-US) scoring system. A post hoc comparative analysis of the joint status of patients with severe haemophilia A (HA) or B (HB) was performed. METHODS: The databases of two observational, cross-sectional studies that recruited patients with HA or HB from 12 Spanish centres were analysed to compare the status of the elbows, knees and ankles in patients with severe disease according to treatment modality. The HEAD-US score was calculated in both studies by the same trained operators. RESULTS: Overall, 95 HA and 41 HB severe patients were included, with a mean age of 35.2 ± 11.8 and 32.7 ± 14.2 years, respectively. The percentage of patients who received prophylaxis, over on-demand (OD) treatment, was much higher in HA (91.6%) than in HB (65.8%) patients. With a similar number of target joints, the HEAD-US score was zero in 6.3% HA and 22.0% HB patients (p < .01), respectively. The HA population showed significantly worse HEAD-US scores. Whilst osteochondral damage occurred more frequently in patients OD or tertiary prophylaxis, our data suggest that articular damage is less prominent in primary/secondary prophylaxis, regardless of the type of haemophilia. These latter treatment modalities were also associated with a lower prevalence of synovial hypertrophy, particularly in HB patients. CONCLUSION: This post hoc analysis indicates that joint status seems to be significantly influenced by haemophilia type (HA or HB) and treatment modality in these severe Spanish populations with severe disease. Continuing HEAD-US monitoring for the early detection and management of intra-articular abnormalities, as well as more efficiently tailored therapies should be warranted.

Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks.

Background: Emicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4). Objectives: Here, we describe pharmacokinetics (PKs), pharmacodynamics (PDs), and exploratory safety biomarkers in HAVEN 1 to 4. Methods: Participants received emicizumab at a loading dose of 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. PKs, PDs, and safety biomarkers were assessed in samples collected at regular intervals during the trials. Results: Emicizumab plasma trough concentrations increased during the loading dose period, reaching a mean of 52.9 µg/mL (SD, 13.6 µg/mL) at week 5, and were sustained at 42.1 to 52.3 µg/mL thereafter with maintenance dosing. Activated partial thromboplastin time shortened following the first emicizumab dose. Mean FVIII-like activity and thrombin generation peak height increased to 25.2 IU/dL (SD, 6.9 IU/dL) and 115.2 nM (SD, 42.5 nM) at week 5, with levels sustained at 17 to 23 IU/dL and >116 nM thereafter, respectively. Emicizumab did not notably affect FIX or FX plasma antigen levels, prothrombin time, or concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen). Conclusion: In HAVEN 1 to 4, emicizumab demonstrated sustained PKs and PDs and improved coagulation parameters without affecting safety biomarkers.

Surgical Experience from the STASEY Study of Emicizumab Prophylaxis in People with Hemophilia A with Factor VIII Inhibitors.

Background Guidelines surrounding emicizumab prophylaxis and perioperative treatment for people with hemophilia A (PwHA) with factor (F)VIII inhibitors undergoing surgeries are limited. The phase IIIb multicenter, single-arm STASEY study evaluated safety and tolerability of emicizumab prophylaxis in PwHA aged ≥12 years with FVIII inhibitors. This analysis assesses surgeries during study conduct, associated hemophilia medications, and postoperative bleeds (treated and untreated). Methods PwHA with FVIII inhibitors received emicizumab 3.0 mg/kg/week for 4 weeks, then 1.5 mg/kg/week until 2 years. Surgeries were managed and documented by treating physicians. Bleeds and treatments were recorded by physicians and participants. Results Forty-six participants had ≥1 on-study surgery, 37 underwent 56 minor surgeries, and 13 underwent 22 major surgeries. Four participants underwent both minor and major surgeries. Of 18 (81.8%) and 4 (18.2%) major surgeries managed with/without additional hemostatic medication, 33.3 and 25.0% were associated with a treated postoperative bleed, respectively. Of 24 (42.9%) and 32 (57.1%) minor surgeries managed with/without additional hemostatic medication, 15.6 and 25.0% were associated with a treated postoperative bleed, respectively. Recombinant activated FVII was the most common medication for prophylaxis and bleed treatment. There were no thrombotic microangiopathies (TMAs). One hypertrophic clot, considered unrelated to emicizumab, occurred following tooth extraction. Conclusion In this challenging population with a high bleeding risk, major surgeries were performed in PwHA receiving emicizumab with/without additional hemostatic medication. Postoperative bleeds occurred following 59.1% of major surgeries; 53.8% were treated. No arterial/venous thrombotic events or TMAs occurred due to concomitant emicizumab and bypassing agents. Trial registration This trial is registered at ClinicalTrials.gov (NCT03191799).

Study of platelet kinetics in immune thrombocytopenia to predict splenectomy response.

Despite the efficacy of splenectomy for chronic immune thrombocytopenia (ITP), its considerable failure rate and its possible related complications prove the need for further research into potential predictors of response. The platelet sequestration site determined by 111 In-labelled autologous platelet scintigraphy has been proposed to predict splenectomy outcome, but without standardisation in clinical practice. Here, we conducted a single-centre study by analysing a cohort of splenectomised patients with ITP in whom 111 In-scintigraphy was performed at La Paz University Hospital in Madrid to evaluate the predictive value of the platelet kinetic studies. We also studied other factors that could impact the splenectomy outcome, such as patient and platelet characteristics. A total of 51 patients were splenectomised, and 82.3% responded. The splenic sequestration pattern predicted a higher rate of complete response up to 12 months after splenectomy (p = 0.005), with 90% sensitivity and 77% specificity. Neither age, comorbidities, therapy lines nor previous response to them showed any association with response. Results from the platelet characteristics analysis revealed a significant loss of sialic acid in platelets from the non-responding patients compared with those who maintained a response (p = 0.0017). Our findings highlight the value of splenic sequestration as an independent predictor of splenectomy response.

Association of patient, treatment and disease characteristics with patient-reported outcomes: Results of the ECHO Registry.

INTRODUCTION: Patient-reported outcomes (PROs) in people living with haemophilia A (PLWHA) are often under-reported. Investigating PROs from a single study with a diverse population of PLWHA is valuable, irrespective of FVIII product or regimen. AIM: To report available data from the Expanding Communications on Haemophilia A Outcomes (ECHO) registry investigating the associations of patient, treatment and disease characteristics with PROs and clinical outcomes in PLWHA. METHODS: ECHO (NCT02396862), a prospective, multinational, observational registry, enrolled participants aged ≥16 years with moderate or severe haemophilia A using any product or treatment regimen. Data collection, including a variety of PRO questionnaires, was planned at baseline and annually for ≥2 years. Associations between PRO scores and patient, treatment and disease characteristics were determined by statistical analyses. RESULTS: ECHO was terminated early owing to logistical constraints. Baseline data were available from 269 PLWHA from Europe, the United States and Japan. Most participants received prophylactic treatment (76.2%), with those using extended-half-life products (10.0%) reporting higher treatment satisfaction. Older age and body weight >30 kg/m2 (>BMI) were associated with poorer joint health. Older age was associated with poorer physical functioning and work productivity. Health-related quality of life and pain interference also deteriorated with age and >BMI; >BMI also increased pain severity scores. CONCLUSION: ECHO captured a variety of disease characteristics, treatment patterns, PROs and clinical outcomes obtained in real-world practice with ≤1 year's follow-up. Older age, poorer joint health and >BMI adversely affected multiple aspects of participant well-being.

Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b open-label trial.

ABSTRACT: Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30-0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors.

Phase 3 Trial of Concizumab in Hemophilia with Inhibitors.

BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).

Clinical efficacy of simoctocog alfa versus extended half-life recombinant FVIII concentrates in hemophilia A patients undergoing personalized prophylaxis using a matching-adjusted indirect comparison method.

OBJECTIVES: We aimed to indirectly compare the efficacy of personalized prophylaxis with simoctocog alfa (Nuwiq®) versus three extended half-life (EHL) recombinant FVIII (rFVIII) concentrates. METHODS: Treatment effects were compared using matching-adjusted indirect comparisons after matching individual patient-level baseline characteristics for simoctocog alfa (pharmacokinetic [PK]-guided personalized prophylaxis) against published aggregate personalized prophylaxis data for efmoroctocog alfa, damoctocog alfa pegol, and rurioctocog alfa pegol. RESULTS: A higher percentage (p < .001) of patients with zero bleeds was found with simoctocog alfa compared with efmoroctocog alfa (75% vs. 45%), damoctocog alfa pegol (77% vs. 38%), and rurioctocog alfa pegol (target trough level 1%-3%; 78% vs. 42%). Similar efficacy was found comparing simoctocog alfa against rurioctocog alfa pegol 8%-12% (77% vs. 62%). The mean total annualized bleeding rate was lower (p < .001) with simoctocog alfa than damoctocog alfa pegol (1.5 vs. 4.9). Consistent with approved dosing, the mean FVIII weekly dose was higher (p < .001) for simoctocog alfa than efmoroctocog alfa, damoctocog alfa pegol, or rurioctocog alfa pegol 1%-3%, but lower (p < .001) than rurioctocog alfa pegol 8%-12%. CONCLUSIONS: Indirect comparisons demonstrated that PK-guided, personalized prophylaxis with simoctocog alfa can lead to higher zero bleed rates compared with personalized EHL rFVIII concentrate regimens, albeit with higher weekly doses, and a lower percentage of patients treated twice weekly or less.

Switching and increasing prophylaxis regimen with a genetically recombinant fusion of coagulation factor IX and albumin in haemophilia B: a case report.

PURPOSE OF REVIEW: We present a case of a boy diagnosed in 2007 with severe haemophilia B [factor IX (FIX) concentration < 1%] at age of 9 months. He was initially treated with recombinant FIX concentrates, but changes in regimens were frequent due to spontaneous hemarthros. In 2013, he entered a phase III trial (NCT01662531) and received rIX-FP, IDELVION at 50 IU/kg once a week. Although the boy was safely maintained with this regimen (2015-2017), the number of hemarthros increased after he started to play football. Thus, rIX-FP regimen was modified (40 IU/kg twice/week) to optimize therapy. This modification was efficient on maintaining patient's thought levels (33%), helped during his fully incorporation at school and social life, and significantly improved synovial hypertrophy. In the last year, the boy has not suffered any bleeding episode and his joint situation improved significantly, which allowed reducing doses to weekly recommended doses. RECENT FINDINGS: FIX replacement therapies with intravenous plasma-derived FIX (pdFIX) or standard half-life recombinant FIX (rFIX) concentrates are hampered by the relatively short terminal elimination half-life (t1/2) of these substances (around 17-34 h), resulting in the need for frequent infusions (e.g. once every 3 or 4 days) to maintain protective FIX levels. In the past years, the first genetically recombinant fusion of rFIX with another protein - a recombinant human albumin - was developed (albutrepenonacog-alfa or rIX-FP; IDELVION) as a strategy to extend the t1/2 of rFIX-FP (around 95 h). SUMMARY: We provide information about the difficult management of a patient with a major bleeding haemorrhagic phenotype, which caused serious limitations in the patient's daily life, impacting his quality of life at his young age, and how the switch to IDELVION allowed the situation to improve considerably.

Simoctocog alfa (Nuwiq®) in previously untreated patients with severe haemophilia A-Final efficacy and safety results from the NuProtect study.

INTRODUCTION: Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors. AIM: To report the efficacy and safety results from the NuProtect study. METHODS: PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study. RESULTS: Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events. CONCLUSION: Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.