IDEAL study: A real-world assessment of pattern of use and clinical outcomes with recombinant coagulation factor IX albumin fusion protein (rIX-FP) in patients with haemophilia B in Italy.

INTRODUCTION: Factor IX replacement therapy is used for treatment and prophylaxis of bleeding in haemophilia B. rIX-FP is an extended half-life albumin-fusion protein, which, in clinical studies, has demonstrated prolonged dosing intervals up to 21 days for routine prophylaxis, providing therapeutic benefit. AIMS: To describe dosing frequency and consumption (primary endpoint), efficacy and safety of rIX-FP treatment during routine clinical practice in Italy. METHODS: Patients with moderate/severe haemophilia B on prophylaxis with rIX-FP for ≥6 months, were enrolled in this observational study from October 2017 to February 2019 and followed-up for 2 years. Descriptive analysis included prospective and retrospective data (12 months prior to switching to rIX-FP). RESULTS: Data were collected from 59 male patients (median age 30.1 years) enrolled by 23 Italian centres. Of them, 50 were on prophylaxis during the entire observation period and completed the study. The infusion frequency changed from 2-3 times/week in 86.0% of patients with previous treatment, to less than once a week in 84.0% of patients treated with rIX-FP at the 2nd-year follow-up. The annual number of infusions decreased by about 70%, whereas the mean FIX activity trough level increased from 3.8% to 14.4% (mean > 10% in all the infusion regimens). Median Annualised Bleeding Rate of .0 was achieved across all prophylaxis regimens. Subjects with zero bleedings increased from 66.0% to 78.0% with rIX-FP. CONCLUSION: Treatment with rIX-FP reduced infusion frequency, while providing higher FIX trough levels with substantial benefit in terms of annualised bleeding rate and a good safety profile.

Efficacy of Replacement and Anti-Platelet Therapies in a Patient with Severe Haemophilia A Undergoing Percutaneous Coronary Stent Implantation.

Introduction: Severe haemophilia A is characterized by serious factor VIII deficiency (biological activity <1%) resulting in frequent spontaneous haemorrhage and abnormal bleeding after minor injury, surgery or tooth extraction. Patient and Methods: We report the case of a 58-year-old patient with severe haemophilia A without inhibitors but with other comorbidities (HCV and HIV seroconversion), who underwent coronary angioplasty and stent implantation after acute myocardial infarction. Results: Compared with previous therapy, Nuwiq® led to a reduction of about 20% in drug consumption (360,000 IU vs 540,000 IU per year) and in the annualized bleeding rate (ABR) (5 vs 15). Discussion: Pharmacokinetic-guided personalized prophylaxis with Nuwiq® provided bleeding protection with good tolerability and a satisfactory pharmacokinetic profile in a patient with severe haemophilia A and comorbidities whose replacement therapy had to be adjusted because of other contraindicated treatment. LEARNING POINTS: Haemophilia A is characterized by frequent haemorrhage.Pharmacokinetic-guided personalized prophylaxis with Nuwiq® provided bleeding protection with good tolerability.Nuwiq® leads to a reduction of about 20% in both drug consumption and the annualized bleeding rate.

Use of the von Willebrand factor concentrate with low factor VIII content to manage patients with inherited von Willebrand disease requiring surgical or secondary long-term prophylaxis: An expert opinion paper from an Italian panel.

OBJECTIVES: The present review aims to summarize the state-of-the-art von Willebrand disease (VWD) treatment focusing on specific clinical settings (obstetrics, surgery, long-term prophylaxis and comorbidities) as well as on the use of a Von Willebrand factor (VWF) concentrate with low FVIII content. METHODS: Literature research and case reports. RESULTS AND CONCLUSIONS: Considering that patients affected by VWD have an intact ability to synthesize FVIII, in order to avoid excessive levels of FVIII, a highly purified plasma VWF concentrate with low FVIII content could be particularly useful in those patients and clinical circumstances at high thrombotic risk as well as for long-term prophylaxis. When deciding the optimal therapeutic strategy, physicians should take into account both the patient's history and the differences among available concentrates according to the clinical situations requiring treatment.

F9 missense mutations impairing factor IX activation are associated with pleiotropic plasma phenotypes.

BACKGROUND: Circulating dysfunctional factor IX (FIX) might modulate distribution of infused FIX in hemophilia B (HB) patients. Recurrent substitutions at FIX activation sites (R191-R226, >300 patients) are associated with variable FIX activity and antigen (FIXag) levels. OBJECTIVES: To investigate the (1) expression of a complete panel of missense mutations at FIX activation sites and (2) contribution of F9 genotypes on the FIX pharmacokinetics (PK). METHODS: We checked FIX activity and antigen and activity assays in plasma and after recombinant expression of FIX variants and performed an analysis of infused FIX PK parameters in patients (n = 30), mostly enrolled in the F9 Genotype and PK HB Italian Study (GePKHIS; EudraCT ID2017-003902-42). RESULTS: The variable FIXag amounts and good relation between biosynthesis and activity of multiple R191 variants results in graded moderate-to-mild severity of the R191C>L>P>H substitutions. Recombinant expression may predict the absence in the HB mutation database of the benign R191Q/W/K and R226K substitutions. Equivalent changes at R191/R226 produced higher FIXag levels for R226Q/W/P substitutions, as also observed in p.R226W female carrier plasma. Pharmacokinetics analysis in patients suggested that infused FIX Alpha distribution and Beta elimination phases positively correlated with endogenous FIXag levels. Mean residence time was particularly prolonged (79.4 h, 95% confidence interval 44.3-114.5) in patients (n = 7) with the R191/R226 substitutions, which in regression analysis were independent predictors (ß coefficient 0.699, P = .004) of Beta half-life, potentially prolonged by the increasing over time ratio between endogenous and infused FIX. CONCLUSIONS: FIX activity and antigen levels and specific features of the dysfunctional R191/R226 variants may exert pleiotropic effects both on HB patients' phenotypes and substitutive treatment.

Emergency management in patients with haemophilia A and inhibitors on prophylaxis with emicizumab: AICE practical guidance in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET.

Emicizumab has been approved in several countries for regular prophylaxis in patients with congenital haemophilia A and FVIII inhibitors because it substantially reduces their bleeding risk and improves quality of life. However, although significantly less frequent, some breakthrough bleeds may still occur while on emicizumab, requiring treatment with bypassing or other haemostatic agents. Thrombotic complications have been reported with the associated use of activated prothrombin complex concentrates. In addition, when surgery/invasive procedures are needed while on emicizumab, their management requires multidisciplinary competences and direct supervision by experts in the use of this agent. Given this, and in order to expand the current knowledge on the use of emicizumab and concomitant haemostatic agents, and reduce the risk of complications in this setting, the Italian Association of Haemophilia Centres (AICE) here provides guidance on the management of breakthrough bleeds and surgery in emergency situations in patients with haemophilia A and inhibitors on emicizumab prophylaxis. This paper has been shared with other National Scientific Societies involved in the field.

Patient satisfaction and acceptability of an on-demand and on-prophylaxis device for factor VIII delivery in patients with hemophilia A.

BACKGROUND: FuseNGO is a relatively new device consisting of a prefilled dual-chamber syringe (DCS) that was recently introduced for the reconstitution of recombinant factor VIII. Herein, the DCS device was assessed using five questionnaires with the primary aim of evaluating patient perceptions and preferences. METHODS: An observational, non-interventional, longitudinal study on 86 patients with a confirmed diagnosis of hemophilia A was carried out at 21 sites in Italy. Each patient underwent a baseline visit and final study visit within 3-6 months. Patients were administered five questionnaires: HemoPREF; Treatment Satisfaction Questionnaire for Medication (TSQM); VeritasPRO; Hemophilia Well-being Index (HWBI); Work Productivity and Activity Impairment Questionnaire (WPAI) + Classroom Impairment Questions (CIQ): Hemophilia Specific (HS). RESULTS: Compared to baseline, scores for HemoPREF were higher at follow-up; significant increases in the percentage of positive responses were seen for all questions regarding the ease of use (P<0.05). The mean time needed for the reconstruction of the device at baseline was 11 minutes (range 1-30 minutes), which decreased to 6 minutes (range 30 seconds to 25 minutes) at follow-up. All scores in the TSQM indicated good satisfaction with the device. Patients reported an adherence of >70% in the VeritasPRO questionnaire, and the majority of patients reported in the HWBI that hemophilia A did not affect their lives in a significant way. The perceived level of overall impairment was 30% as reported in the WPAI + CIQ: HS, indicating little impairment. There were no safety concerns. CONCLUSION: Considering patient-reported outcomes, the DCS device was associated with easier preparation, storage, disposal of equipment, and overall use. Of particular note, preparation times were reduced by around 50%. The majority of patients were satisfied with the device and overall adherence scores were high. Considering these results, the device has the potential to increase adherence to therapy and, possibly, reduce healthcare costs.

Current challenges in the diagnosis and management of patients with inherited von Willebrand's disease in Italy: an Expert Meeting Report on the diagnosis and surgical and secondary long-term prophylaxis.

Recent advances in the care of von Willebrand's disease (vWD) have allowed the majority of patients to be managed adequately. Even in the more severe forms, it is now possible to control recurrent bleeding through secondary long-term prophylaxis with von Willebrand factor-containing concentrates. Moreover, in the setting of surgical prophylaxis, the combination of interdisciplinary management and close patient monitoring yields a positive outcome in nearly all cases, although safety concerns remain. In clinical practice, the effectiveness of therapy is hindered by the difficulties in making a rapid, yet accurate diagnosis, in identifying the subgroup of bleeders who may benefit most from a specific strategy, and in selecting the optimal product and regimen.Since specific guidelines for heavy bleeders requiring short- and long-term prophylaxis are still lacking, sharing the experience of experts dealing with vWD patients on a daily basis is crucial to fill gaps in information relating to patient management. To address this important issue, 13 Italian haematologists met in Milan on April, 2, 2016 and in Florence on July, 9, 2016. A 30-question survey constituted the input to discuss (i) optimisation of the diagnostic workflow for vWD, (ii) the characteristics of patients who may benefit from secondary long-term prophylaxis (in particular with the purified von Willebrand factor concentrate with a low content of factor VIII), (iii) the key elements to consider when selecting a concentrate and (iv) the pre-operative and post-operative management of vWD patients. A summary of the main points covered is provided in this report.

Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study.

Rigorous evidence is lacking on long-term outcomes of factor VIII (FVIII) prophylaxis initiated in adolescent or adult patients with severe haemophilia A. The prospective, open-label Prophylaxis versus On-demand Therapy Through Economic Report (POTTER) study (ClinicalTrials.gov NCT01159587) compared long-term late secondary prophylaxis (recombinant FVIII-FS 20-30 IU/kg thrice weekly) with on-demand treatment in patients aged 12 to 55 years with severe haemophilia A. The annual number of joint bleeding episodes (primary endpoint), total bleeding episodes, orthopaedic and radiologic (Pettersson) scores, health-related quality of life (HRQoL), pharmacoeconomic impact, and safety were evaluated over a > 5-year period (2004-2010). Fifty-eight patients were enrolled at 11 centres in Italy; 53 (27 prophylaxis, 26 on demand) were evaluated and stratified into 2 age subgroups (12-25 and 26-55 years). Patients receiving prophylaxis experienced a significantly lower number of joint bleeding episodes vs the on-demand group (annualised bleeding rate, 1.97 vs 16.80 and 2.46 vs 16.71 in younger and older patients, respectively; p=0.0043). Results were similar for total bleeding episodes. Prophylaxis was associated with significantly fewer target joints (p< 0.001), better orthopaedic (p=0.0019) and Pettersson (p=0.0177) scores, better HRQoL, and fewer days of everyday activities lost (p< 0.0001) but required significantly higher FVIII product consumption. The POTTER study is the first prospective, controlled trial documenting long-term benefits of late secondary prophylaxis in adolescents and adults with severe haemophilia A. The benefits of reduced bleeding frequency, improved joint status, and HRQoL may offset the higher FVIII consumption and costs.

Cost-consequence analysis of long-term prophylaxis in the treatment of von Willebrand disease in the Italian context.

PURPOSE: Prophylaxis with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates is a potential approach for patients with severe von Willebrand disease (VWD). As far as we are aware, to date there have been no pharmacoeconomic analyses in order to assess the economic impact of treatments for severe VWD. The analysis presented here estimates the cost-benefit ratio of VWF with a low FVIII content when compared with VWF/FVIII concentrates currently used in Italy for long-term prophylaxis in patients with severe VWD. METHODS: A cost-consequence analysis was undertaken to assess the economic impact of the treatment of severe VWD from the perspective both of the Italian National Health Service and society. The analysis was based on four case reports of long-term prophylaxis with VWD with VWF/FVIII concentrates and VWF with a low FVIII content. The costs per patient included direct and indirect costs for each treatment. RESULTS: Considering the four case reports, health care costs (without cost of treatment) and indirect costs per patient per year were lower with VWF with a low FVIII content than VWF/FVIII concentrates. The total health care costs (without cost of treatment) and indirect costs avoided with VWF with a low FVIII content per patient per year ranged from €2,295 to €17,530 and from €1,867 to €4,978, respectively. CONCLUSION: VWF with a low FVIII content seems to be a cost-effective treatment option for patients with severe VWD. Although the drug cost per se is higher, the use of VWF with a low FVIII content is associated with decreased consumption of hospital resources and fewer lost working days due to bleedings and consequently with an improvement of the quality of life of the patients.