Real-World Bleeding Outcomes, Weekly Factor Consumption Doses, Annualized Factor Costs in Severe-Type Patients with Hemophilia a (PwHA) before and after Switching to Extended Half-Life rFVIII-Fc Prophylaxis

Abstract Introduction: Stand half-life (SHL) rFVIII had been used in patients with hemophilia A (PwHA) for episodic treatment (ET) and prophylaxis therapy (PT) for years. Extended half-life (EHL) rFVIII had been available since 2014, also available in Taiwan since 2018, and resulted in markedly increased willingness for PT because it reduced injection burden. We aimed to investigate the real-world bleeding outcomes, weekly factor doses, and factor costs of severe-type PwHA with pre-switch SHL rFVIII and post-switch EHL rFVIIIFc prophylaxis in Taiwan, and made a pre-switch and post-switch comparison. Methods and Materials: There were totally 51 non-inhibitor, severe-type PwHA, with complete bleeding records before and after switching from SHL rFVIII to EHL rFVIII-Fc, enrolled from two hemophilia centers during Nov, 2018－July, 2019. Most of them had various degree of one to more major joints arthropathy, except children. The medical charts were retrospective reviewed and data were collected, including body features and factor regimen, etc. Patients' annualized bleeding/joint-bleeding rate (ABR/AJBR), weekly doses (WD), annualized factor costs (AFC) were obtained from the chart records of pre-switch 12 months and post-switch at least more-than 6-month until July, 2019. Data from scheduled operation or hospitalization due to trauma or accidence were excluded. Results: There were 8 boys and 43 adults, the median age of all PwHA when switching was 35.6 years (10.5-62). Before switching, these 51 PTP treated with SHL rFVIII who received ET (ET group), irregular prophylaxis (IP group), and regular prophylaxis (RP group) were 19 (37.3%), 7 (13.7%), and 25 (49%), respectively. Bleeding records of 51 PTP treated with SHL rFVIII were traced back with 11.8±0.9 months. After switching to rFVIII-Fc, 3 PwHA receiving ET were excluded, and bleeding records of 48 received RP were obtained with 14.7±4.6 months. Pre-switch and post-switch prophylaxis rate were 62.7% (32/51) and 94.1% (48/51), respectively. For comparison of pre-switch and post-switch outcomes: Median ABR was reduced from 48, 12, and 4 to 1.15, 1.9, and 1.5 for ET, IP, and RP group, respectively. Median AJBR was reduced from 32, 11, and 4 to 0.95, 0.7, and 1.2 for ET, IP, and RP group, respectively. Median WD was increased from 38.4, 52.9, and 63.6 IU/kg/wk to 84.6, 84.5, and 84.9 IU/kg/wk for ET, IP, and RP group, respectively. Median AFC was increased from 4,141,800, 4,064,000 and 5,129,700 NTD to 7,042,325, 5,835,450, and 5,762,810 NTD for ET, IP, and RP group, respectively. Comparing pre-switch and post-switch outcomes of children and adults who received pre-switch and post-switch prophylaxis, median ABR was reduced from 3 and 5 to 1.35 and 1.85 for children and adults, respectively. Median AJBR was reduced from 3 and 4 to 1.35 and 1.15 for children and adults, respectively. Median WD was increased from 58.8 and 58.3 IU/kg/wk to 87.85 and 83.85 IU/kg/wk for children and adults, respectively. Median AFC was increased from 4,104,225 and 5,879,025 NTD to 4,419,800 and 6,024,916 NTD for children and adults, respectively. For all PwHA, zero ABR accounted for 5.9% (3/51) with pre-switch SHL rFVIII treatment and for 20.8% (10/48) with post-switch rFVIII-Fc prophylaxis. Zero AJBR accounted for 9.8% (5/51) with SHL rFVIII treatment and for 33.3% (16/48) with rFVIII-Fc prophylaxis. For PwHA with pre- and post-switch prophylaxis, zero ABR accounted for 12.5% (1/8) and 8.3% (2/24), respectively, for children and adults on SHL rFVIII prophylaxis and 25% (2/8) and 25% (6/24) respectively, for children and adults on rFVIII-Fc prophylaxis. Zero AJBR accounted for 12.5% (1/8) and 16.7% (4/24), respectively, for children and adults on SHL rFVIII prophylaxis and 25% (2/8) and 37.5% (9/24) respectively, for children and adults on rFVIII-Fc prophylaxis. Conclusion: In real-world setting, for pre-switch ET group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR reduced >95%, and mean WD increased >50%. For pre-switch IP group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR reduced >80%, and mean WD increased >35%. For pre-switch RP group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR also reduced >45%, and mean WD increased >20%. The proportions in zero ABR and zero AJBR as post-switch rFVIII-Fc prophylaxis were increased. No matter in ET, IP, or RP group, after switching to RP with rFVIII-Fc, improvement for bleeding outcomes was quite evident. Disclosures No relevant conflicts of interest to declare.

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Analysis of US Claims Real World Data of Hemophilia a & B Patients: Units Dispensed & Expenditures Associated with Utilization of and Switching from Standard to Extended Half-Life Factor Products

Blood ◽

10.1182/blood-2018-99-119133 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3508-3508

Author(s):

Bartholomew J. Tortella ◽

Amit Chhabra ◽

José Alvir ◽

Emily R. Rubinstein ◽

Lisa J. Young ◽

...

Keyword(s):

Real World ◽

Half Life ◽

Hemophilia A ◽

Real World Data ◽

World Data ◽

Treatment Scheme ◽

Before And After ◽

Male Patients ◽

The Impact ◽

Life Factor

Abstract Background: Both standard half-life (SHL) and extended half-life (EHL) factor replacement products are used to treat patients with hemophilia A (hem-A) and B (hem-B). A comparison of international unit (IU) utilization and expenditures ($USD) was made between patients on SHL and EHL factor replacement products to compare utilization and to determine the impact of switching from an SHL to an EHL product. Methods: De-identified claims data from both the Truven Health MarketScan® Research (Truven) and Optum® Clinformatics® (Optum) US claims databases included male patients with hem-A (Truven from Aug 2014-Apr 2018 and Optum from Aug 2014-Dec 2017) and hem-B (Truven from Jun 2014-Apr 2018 and Optum from Jul 2014-Dec 2017) who had data for at least 3 months of product dispensation. The SHL and EHL groups were compared. A separate "switch" analysis using the Truven database examined expenditures and IUs before and after switching from nonacog-α (SHL) to FIX-Fc (EHL). Descriptive statistics were used and medians reported for expenditures and IUs to accommodate for the skewness of data distribution. Results: Hem-A: The analysis included 896 SHL and 202 EHL patients, including those who switched from an SHL to an EHL product. Quarterly expenditures and IUs dispensed were analyzed. Both the Optum and Truven databases (see Table) demonstrated higher IU dispensation (Optum: 35%, Truven: 50% higher) and expenditures (Optum: 87%, Truven: 117%) associated with EHL products versus SHL products. In the switch analysis, 35 patients switched from nonacog-α to FIX-Fc; median IUs rose from 61,228 to 75,914 [24%] and median expenditures rose from $78,945 to $155,203 [97%]. Hem-B: The analysis included 50 FIX-Fc, 13 FIX-Alb, and 132 nonacog-α patients. Both databases (see Table) demonstrated higher median expenditures for the EHL products compared with nonacog-α (Optum: 179% for FIX-Fc, 189% for FIX-Alb; Truven: 234% for FIX-Fc, 245% for FIX-Alb). The IU results varied in Optum: FIX-Fc was 23% higher than nonacog-α, but FIX-Alb was 9 % lower than nonacog-α. Similarly, in Truven, the IU results varied: IUs were mixed for the SHL product compared with the EHL products: 62% higher for FIX-Fc than nonacog-α, and approximately the same for FIX-Alb and nonacog-α. In the switch analysis, 16 patients switched from nonacog-α to FIX-Fc; median IUs rose from 62,857 (nonacog-α) to 69,816 (FIX-Fc) [11%], while expenditures rose from $75,064 (nonacog-a) to $210,482 (FIX-Fc) [180%]. Conclusions: This analysis in more than 1000 patients, unadjusted for severity of disease or treatment scheme, demonstrated in hem-A that higher IU utilization and expenditures were associated with EHL use compared with SHL use, and in hem-B, that higher expenditures were seen with EHL products, while IU dispensation in some cases decreased, remained the same, or increased. In patients switching from the SHL to an EHL product, higher IU dispensation and expenditures were seen. These real-world data may challenge assumptions regarding typical factor usage and expenditures associated with EHL products in patients with hem-A and hem-B. Additional analyses with adjustment for treatment scheme and disease severity are needed. Table. Table. Disclosures Tortella: Pfizer Inc.: Employment. Chhabra:Pfizer Inc.: Employment. Alvir:Pfizer Inc.: Employment. Rubinstein:Pfizer Inc.: Employment. Young:Pfizer Ltd.: Employment. Fogarty:Pfizer Inc.: Employment.

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Real-World Age-Stratified FVIII Consumption and Bleed Outcomes Before and After Switching to Rurioctocog Alfa Pegol in a Retrospective, Observational Study Using US Specialty Pharmacy Data

Blood ◽

10.1182/blood-2019-124101 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2411-2411

Author(s):

Maureen Watt ◽

Scott Milligan

Keyword(s):

Clinical Trial ◽

Real World ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

The United States ◽

Patient Data ◽

Severe Hemophilia ◽

Before And After ◽

Pharmacy Data

Introduction: The safety and efficacy of rurioctocog alfa pegol (BAX 855, SHP-660, TAK-660; Adynovate®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in patients with severe hemophilia A has been reported previously (Konkle BA et al., Blood 2015, 126:1078-85; Brand B et al., Haemophilia 2016, 22:e251-8; Mullins ES et al., Haemophilia 2017, 23:238-46); however, research describing patient experience with extended half-life (EHL) recombinant factor VIII (FVIII) products outside clinical trials is limited. The objective of this study was to assess real-world utilization of TAK-660 in patients with hemophilia A and describe their clinical profiles before and after switching to TAK-660. Factor consumption and bleed outcomes stratified by age (<18 and ≥18 years) are reported herein. Methods: This was a retrospective, observational database study of patient data from US specialty pharmacies. Pharmacy data sources included patient records, prescriptions, and patient-reported bleed logs. Informed consent was obtained for all analyzed patient data. Eligible patients with hemophilia A were treated with prophylactic TAK-660 with on-label dosing from November 2015 to September 2018, and had received ≥90 days of FVIII (standard half-life [SHL] or EHL) therapy before switching to TAK-660. Main exclusion criteria were participation in a TAK-660 clinical trial before/during this study, only on-demand treatment before switching to TAK-660, or presence of active FVIII inhibitor requiring treatment and/or use of immune tolerance induction during the study period. Assessments included prior hemophilia therapy, FVIII administration frequency and consumption, and annualized bleeding rate (ABR) before and after switching to TAK-660. Results: Data was collected from 82 patients (of 61 providers in 44 practices across 25 states in the United States): 44% of the patients (36/82) were <18 years old; 56% (46/82) were ≥18 years old (none were ≥60 years old); 83% (68/82) had severe hemophilia A; and 88% (72/82) had received prior SHL-FVIII treatment. The SHL antihemophilic factor (recombinant) (Advate®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) was used by 67% (55/82) of patients overall, of whom 47% (26/55) were <18 years old and 53% (29/55) were ≥18 years old. Compared with any prior FVIII therapy, switching to TAK-660 increased FVIII dose per administration in patients <18 and ≥18 years old (+39.5% and +22.9%, respectively), while their weekly administration frequency decreased (-21.4% and -28.1%, respectively; Table 1). Weekly FVIII consumption increased in patients aged <18 years (+11.2%) and decreased in those aged ≥18 years (-12.8%). FVIII administration frequency and consumption by prior SHL- or EHL-FVIII are reported in Table 1. ABR data before and after switching were available in 47 of 82 patients. Compared with any prior FVIII therapy, mean ABR decreased in patients aged <18 years (-39.5%; 2.8 to 1.7) and ≥18 years (-50.3%; 3.4 to 1.7) with TAK-660 treatment (Table 2). Changes in mean ABR by prior FVIII therapy and disease severity are reported in Table 2. The small number of patients who received prior EHL FVIII was a limiting factor in the comparison of patients who received prior SHL- and EHL-FVIII therapy. Conclusions: In patients with hemophilia A previously treated with SHL- or EHL-FVIII products, switching to TAK-660 prophylaxis resulted in a significant decrease in ABR of 40-50% in both age groups analyzed. The adult population (ie, ≥18 years old) showed a tendency for reduced weekly FVIII consumption. These findings from real-world data are in agreement with TAK-660 clinical trial results. The observed differences in FVIII consumption between patients <18 and ≥18 years old may have been in part a result of age-related changes in bleeding patters, growth, and other factors. Disclosures Watt: Shire International GmbH, a Takeda company: Employment, Other: a Takeda stock owner. Milligan:Sanofi: Research Funding; Merck: Research Funding; Gilead: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Trio Health: Employment; Viiv: Research Funding.

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Baseline VWF:Ag Level and Body Mass Index Are Inverse Influencing Factors of Annualized Total Bleeding Rate and Annualized Joint Bleeding Rate Respectively in Severe-Type Adult Patients with Hemophilia a (PwHA) with Episodic Treatment with rFVIII

Blood ◽

10.1182/blood-2021-150822 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3199-3199

Author(s):

Chia-Yau Chang ◽

Shiue-Wei Lai ◽

Mei-Mei Cheng ◽

Jung-Tzu Ku ◽

Shu-Hsia Hu ◽

...

Keyword(s):

Body Mass Index ◽

Blood Group ◽

Influencing Factors ◽

Body Mass ◽

Hemophilia A ◽

P Value ◽

Weekly Dose ◽

Bleeding Rate ◽

Episodic Treatment ◽

Severe Type

Abstract Introduction: Bleeding phenotypes of severe-type patients with hemophilia A (PwHA) vary greatly, which influence factor consumption and medical cost. Factors affecting bleeding patterns of PwHA include various procoagulant and anticoagulant factors, joint condition and physical activity, etc. We aimed to investigate clinical factors influencing by-nature bleeding frequency of severe-type PwHA during episodic treatment. Methods and materials: There were 19 non-inhibitor, severe-type, previously treated PwHA aged >20 years, who had at least one to five major joints arthropathy, retrospectively enrolled from two hemophilia centers for analysis. They had been refusing prophylaxis therapy with FVIII product due to heavy burden of frequent intravenous FVIII injection and had long-term episodic treatment. Clinical informations were collected from November 2017 to November 2018, including age, body mass index (BMI), body weight, ABO blood grouping, HCV and HIV infection status, baseline VWF:Ag and VWF:activity, mutation of F8 gene. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR), weekly doses and annualized factor consumption costs (calculated by new Taiwan dollars, NTD) were obtained from the patients' medical records. Results: The PwHA with ABR <24 had significantly lower proportion of blood-group-O patients, higher baseline VWF:Ag and VWF:activity than those with ABR >24.(P-value <0.05) The PwHA with AJBR <13 had significantly higher BMI than those with AJBR >13.(P-value <0.05) There was no significant difference in ABR, AJBR, weekly dose, and annualized factor cost between PwHA with O blood group and non-O blood group. Compared with PwHA with baseline VWF:Ag or VWF:activity <145%, those with baseline VWF:Ag or VWF:activity >145% had significantly older age (34.9 vs 53.2 years, P-value <0.05), higher BMI (25.2 vs 29.9, P-value <0.05), lower ABR (58.2 vs 12.2 per year, P-value<0.01), lower AJBR (46.8 vs 10.8 per year, P-value<0.01), lower weekly dose (42.4 vs 10.6 IU/kg/wk, P-value<0.01), and lower annualized factor consumption costs (4,177,732 vs 1,120,704 NTD, P-value<0.01). Compared with PwHA with BMI <28, those with BMI >28 had significantly lower ABR (58.2 vs 12.2 per year, P-value<0.05), lower AJBR (46.8 vs 10.8 per year, P-value<0.05), higher baseline VWF:activity (94.6% vs 190.2%, P-value <0.05), and lower weekly dose (38.5 vs 17.1 IU/kg/wk, P-value <0.05). By backward-stepwise multivariate linear regression, baseline VWF:Ag and BMI were identified as independent and significant inverse influencing factors for ABR and AJBR, respectively.(P-value <0.05) Conclusion: For severe-type adult PwHA with episodic treatment, baseline VWF:Ag or VWF:activity >145% was associated with lower ABR, AJBR, weekly dose, and annualized factor cost. BMI >28 was associated with lower ABR, AJBR, and weekly dose consumption. Baseline VWF:Ag and BMI were revealed as inverse influencing factors for ABR and AJBR, respectively. The results of our study could be useful for clinicians to have an insight into diversity of bleeding phenotypes of by-nature severe-type PwHA. For developing countries where factor concentrate resources are not enough, these clinical influencing factors might be helpful for the management of therapeutic strategies and resource allocation for severe PwHA. Disclosures No relevant conflicts of interest to declare.

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Effects of replacement therapies with clotting factors in patients with hemophilia: A systematic review and meta-analysis

PLoS ONE ◽

10.1371/journal.pone.0262273 ◽

2022 ◽

Vol 17 (1) ◽

pp. e0262273

Author(s):

Carolina J. Delgado-Flores ◽

David García-Gomero ◽

Stefany Salvador-Salvador ◽

José Montes-Alvis ◽

Celina Herrera-Cunti ◽

...

Keyword(s):

Low Dose ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Clotting Factor ◽

High Dose ◽

Bleeding Rate ◽

Episodic Treatment ◽

Grade Methodology ◽

Inform Decision Making ◽

Intermediate Dose

Background Different prophylactic and episodic clotting factor treatments are used in the management of hemophilia. A summarize of the evidence is needed inform decision-making. Objective To compare the effects of factor replacement therapies in patients with hemophilia. Methods We performed a systematic search in PubMed, Central Cochrane Library, and Scopus. We included randomized controlled trials (RCTs) published up to December 2020, which compared different factor replacement therapies in patients with hemophilia. Random-effects meta-analyses were performed whenever possible. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The study protocol was registered in PROSPERO (CRD42021225857). Results Nine RCTs were included in this review, of which six compared episodic with prophylactic treatment, all of them performed in patients with hemophilia A. Pooled results showed that, compared to the episodic treatment group, the annualized bleeding rate was lower in the low-dose prophylactic group (ratio of means [RM]: 0.27, 95% CI: 0.17 to 0.43), intermediate-dose prophylactic group (RM: 0.15, 95% CI: 0.07 to 0.36), and high-dose prophylactic group (RM: 0.07, 95% CI: 0.04 to 0.13). With significant difference between these subgroups (p = 0.003, I2 = 82.9%). In addition, compared to the episodic treatment group, the annualized joint bleeding rate was lower in the low-dose prophylactic group (RM: 0.17, 95% CI: 0.06 to 0.43), intermediate-dose prophylactic group (RM of 0.14, 95% CI: 0.07 to 0.27), and high-dose prophylactic group (RM of 0.08, 95% CI: 0.04 to 0.16). Without significant subgroup differences. The certainty of the evidence was very low for all outcomes according to GRADE methodology. The other studies compared different types of clotting factor concentrates (CFCs), assessed pharmacokinetic prophylaxis, or compared different frequencies of medication administration. Conclusions Our results suggest that prophylactic treatment (at either low, intermediate, or high doses) is superior to episodic treatment for bleeding prevention. In patients with hemophilia A, the bleeding rate seems to have a dose-response effect. However, no study compared different doses of prophylactic treatment, and all results had a very low certainty of the evidence. Thus, future studies are needed to confirm these results and inform decision making.

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Clinical Predictors and Prediction Models for Frequency of Total and Joint Hemorrhage in Severe-Type Patients with Hemophilia a (PwHA) with/without Intermediate-Dose Prophylaxis Therapy with rFVIII

Blood ◽

10.1182/blood-2021-147069 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1047-1047

Author(s):

Chia-Yau Chang ◽

Shiue-Wei Lai ◽

Mei-Mei Cheng ◽

Jung-Tzu Ku ◽

Shu-Hsia Hu ◽

...

Keyword(s):

Hiv Infection ◽

Treatment Modality ◽

Prediction Models ◽

Hcv Infection ◽

Treatment Model ◽

Bleeding Rate ◽

Hcv Antibody ◽

The Mean ◽

Prophylaxis Therapy ◽

Severe Type

Abstract Introduction: It was well-known that severe-type patients with hemophilia A (PwHA) had great variability in bleeding phenotypes. Factors effecting bleeding patterns of PwHA include at least treatment modality and interindividual various procoagulant and anticoagulant levels. We aimed to investigate what clinical variables could predict bleeding frequency of severe PwHA and to develop models for predicting bleeding phenotypes among severe PwHA with/without FVIII prophylaxis therapy. Methods and materials: Totally 51 severe-type previously-treated PwHA from two Hemophilia Centers in Taiwan were enrolled, who received standard half life (SHL) rFVIII products with complete consecutive bleeding records at least more than 6 months, and their medical charts 2017－2018 were retrospectively viewed. The clinical data were collected for analysis, including age, body mass index (BMI), body weight (BW), ABO blood groups, hemoglobin (Hb), hematocrit (Hct), HCV infecton, HIV infection, treatment modality, baseline VWF levels, and genetic defects. Baseline VWF activity meant the data via VWF:ACL activity or VWF:RCo. Clinical variables for annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were evaluated by multivariate linear regression (MVLR) analysis. Results: The cohort of 51 severe-type PwHA included 8 boys and 43 adults, aged 8-64. For treatment modality, there were 19 patients receiving episodic treatment (ET) and 32 receiving prophylaxis therapy (PT) with intermediate-dose standard half life (SHL) rFVIII. The mean study period was 11.9 months, range 10－14.5 months. Among them, there were 31 with HCV infection and 4 with HIV infection. PwHA with non-O blood group were 31 and those with O blood group 20. The mean baseline VWF:Ag was 115.6±55.5%, range 50%－294.7%. The mean baseline VWF:activity was 105.4±52.1%, range 41.3%－307%. ABR of ET group and PT group were 46.1±29.2 and 6.8±7.1, respectively. (p<0.0001***) AJBR of ET group and PT group were 37.3±27.7 and 6.0±6.8, respectively. (p=0.0001***) By MVLR analysis, both treatment modality and baseline VWF:Ag were recognized as inverse predictors of ABR and AJBR, and HCV infection recognized a predictor for AJBR. Age, inhibitor histroy, BMI, BW, ABO blood groups, Hct, Hb, HIV infection, and missense mutation or not were eliminated as predictors. The predictive equations by MVLR were as the following two: (1) Predictive ABR = 56.5 - 37.8 * (Treatment model) - 11.8 * baseline VWF:Ag (IU/mL). (2) Predictive e AJBR = 41.9 - 28.6 * (Treatment model) - 12.0 * baseline VWF:Ag (IU/mL) + 10.0 * (HCV infection). (1 if Treatment model is PT, 0 if Treatment model is ET. 1 if HCV infection or anti-HCV antibody is positive, 0 if HCV infection or HCV antibody is negative.) Separate prediction models developed from MVLR analysis could explain 52.51% of the ABR variability and 50.56% of the AJBR variability. The correlation between predicted and observed bleeding frequency was significantly strong.(P-rank>0.7, p-value<0.0001***) Mean difference between predicted ABRs and observed ABRs was 1.75 and that between predicted AJBRs and observed AJBRs was 1.27. Predicted ABR deviated <21 (<2 per month) of observed ABR in 42/50 patients (84%). Predicted AJBR deviated < 24 (<2 per month) ofobserved AJBR in 44/50 patients (88%). Conclusion: Prophylaxis therapy and baseline VWF:Ag levels were the strongest two inverse predictors for ABR and AJBR. Positive HCV infection was another predictor for AJBR. The prediction models provided with an insight into personal bleeding quantified patterns and may identify PwHA with high bleeding risks based on individual characteristics of treatment modality, baseline VWF:Ag, and HCV infection. Our approach is of help for individualized treatment and refining of dosing strategies. Disclosures No relevant conflicts of interest to declare.

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Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽

10.1182/blood-2019-127270 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2409-2409

Author(s):

Tiffany Lin Lucas ◽

Shveta Gupta ◽

Joanna A. Davis ◽

Fernando F. Corrales-Medina

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hemophilia A ◽

The United States ◽

Haemophilia A ◽

Advisory Committees ◽

Inhibitor Development ◽

Increased Risk ◽

Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

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Real Life Experience in Clinical Practice with Recombinant Coagulation FVIII-Fc Fusion Protein

Blood ◽

10.1182/blood-2019-127878 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4929-4929

Author(s):

Teresa Álvarez Roman ◽

Elena Monzón Manzano ◽

Ihosvany Fernandez-Bello ◽

Mónica Martín ◽

María Isabel Rivas Pollmar ◽

...

Keyword(s):

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Trough Level ◽

Real Life ◽

University Hospital ◽

Severe Hemophilia ◽

Median Dose ◽

La Paz ◽

Before And After

Introduction: Efmoroctocog alfa (Elocta®) is a recombinant coagulation FVIII-Fc (rFVIIIFc), a fully recombinant fusion protein produced in human embryonic kidney cells, with an extended half-life used for the treatment and prevention of bleeding in patients with severe hemophilia A. Using rFVIIIFc for the treatment of severe hemophilia A patients received the approval of reimbursement in Spain at the end of 2016. Therefore, there are no many comparative data published about real life use of rFVIIIFc. Objective: This work aims to describe characteristics of the treatment of severe hemophilia A patients with rFVIIIFc and to compare its results with those previously obtained employing other FVIII products. Methods: This was an open-label non-interventional retrospective study reviewing patient characteristics and treatment outcomes before and after the use of rFVIIIFc. The La Paz University Hospital Ethics Committee approved the experimental protocol. Patients with severe hemophilia A without inhibitors being treated with rFVIIIFc since at least six months before study approval by Ethics Committee were included. The following data were collected for patients included in the study: dose (IU/kg) and prophylaxis treatment regimen, number of spontaneous and traumatic bleedings, annual bleeding rate (ABR) and FVIII trough level. The statistical analysis on the variables listed above comparing before and after rFVIIIFc usage was performed by the Biostatistics Unit of La Paz University Hospital with the statistical package SPSS v.18.0 (SPSS Inc., Chicago, IL, USA). Results: Twenty two severe hemophilia A patients (median age: 20 years old, ranging from 6 to 63 years) on prophylaxis with rFVIIIFc were considered to be included in this study, but two were excluded due to lack of data. Median follow-up period was 14 months (ranging from 6 to 28 months). Nineteen severe hemophilia A patients have been previously treated with rFVIII (two of them with other extended half-life product) and one with plasma-derived FVIII. Eight of the ten severe hemophilia A patients who presented an ABR greater than 0 with previous treatments reduced their ABR when treated with rFVIIIFc (Table 1). Among those patients with an ABR=0 with previously used FVIII products, only one increased to an ABR=1 when treated with Elocta® due to a traumatic bleeding. Table 1 shows ABR across all patients before and after rFVIIIFc. There was no difference in dose per injection between other FVIII products and rFVIIIFc (median dose for patients treated with other FVIII products: 46.0 IU/kg, ranging from 26 to 65 IU/kg; median dose for patients treated with rFVIIIFc: 46.5 IU/kg, ranging from 26 to 65 IU/kg). Nevertheless, a reduction was observed in administration frequency. Among the twelve patients who received treatment with other FVIII products every 48 hours, eleven came to receive rFVIIIFc 3 times a week and the one previously receiving a plasma-derived FVIII, to twice a week. Five of the patients receiving treatment 3 times a week reduced its frequency to twice per week. Three patients maintained the same schedule of administration. To note, one of the two patients receiving another prolonged half-life product maintained the schedule of treatment and the other reduced its frequency from every 48 hours to 3 times a week. FVIII trough level in plasma (% of FVIII), expressed as median (25th-75th percentile), was 1.1 (0.1-4.0) for rFVIIIFc treatment and 0.2 (0.0-1.9) for other FVIII products (p=0.06). Conclusions: 85% of the severe hemophilia A patients from our cohort reduced the weekly dose administration after beginning treatment with rFVIIIFc. Most of the patients increased plasma trough level of FVIII with rFVIIIFc. 45% of patients reduced and 40% kept their ABR=0 when they changed rFVIIIFc. These data suggest that treatment with rFVIIIFc gives a higher protection to severe hemophilia A patients. However, further research with larger sample size is required to investigate this. This work was supported by SOBI. NB holds a tenure track grant from FIS-FONDOS FEDER (CP14/00024). Disclosures Álvarez Roman: Takeda: Research Funding; Amgen: Consultancy, Speakers Bureau; NovoNordisk: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau. Fernandez-Bello:Novartis, Pfizer, ROCHE, Stago: Speakers Bureau. Martín:SOBI: Research Funding; Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau. Rivas Pollmar:Novartis, Pfizer, ROCHE, Novo Nordisk: Speakers Bureau; SOBI: Research Funding. García Barcenilla:Bayer, Pfizer, Takeda, Novartis: Speakers Bureau; SOBI: Research Funding. Canales:SOBI: Research Funding; iQone: Honoraria; Karyopharm: Honoraria; Novartis: Honoraria; Takeda: Speakers Bureau; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Sandoz: Honoraria. Butta:Roche, Pfizer: Speakers Bureau; Novartis: Consultancy. Jimenez-Yuste:Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, Shire: Consultancy, Honoraria, Other: reimbursement for attending symposia/congresses , Research Funding, Speakers Bureau.

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Straightforward Transition to Bay 81-8973 Prophylaxis in Patients with Hemophilia A: Prospective Real-World Data from the Taurus Non-Interventional Study Show That Number of Infusions per Week Is Maintained or Reduced

Blood ◽

10.1182/blood-2018-99-116622 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5045-5045

Author(s):

Michael Wang ◽

Beng Fuh ◽

Philip Maes ◽

Maria Eva Mingot-Castellano ◽

Rubén Berrueco ◽

...

Keyword(s):

Clinical Trials ◽

Real World ◽

Hemophilia A ◽

Weekly Dose ◽

Real World Data ◽

World Data ◽

Real World Setting ◽

Patient Reported ◽

Dosing Frequency

Abstract BACKGROUND: BAY 81-8973 (Kovaltry®, Bayer) is an unmodified full-length recombinant FVIII indicated for prophylaxis and treatment of bleeds in patients with hemophilia A; BAY 81-8973 was launched in 2016 and has since accumulated 6765 patient-years of exposure. The TAURUS study (NCT02830477) was established to investigate BAY 81-8973 prophylaxis dosing regimens chosen in clinical practice and confirm the established safety and efficacy results from the LEOPOLD clinical trials in a real world setting. OBJECTIVES: To analyse the proportion of patients on specific BAY 81-8973 prophylaxis regimens, bleeds, and patient-reported outcomes at baseline and most recent follow-up. METHODS: TAURUS is an international, open label, prospective, non-interventional, single arm study with a target recruitment of 350 previously treated patients with hemophilia A of all ages with moderate or severe hemophilia A (≤ 5% FVIII:C) with ≥ 50 exposure days to any FVIII product who have been switched to prophylaxis with BAY 81-8973. At baseline, physicians document clinical information including age, BMI, severity of hemophilia, number of target joints, prior treatment regimen, bleed history, inhibitor history, and reason for choosing a specific prophylaxis regimen. Patients/caregivers reported bleeds in ongoing patient diaries, and completed questionnaires on treatment satisfaction (HEMOSAT) and adherence (VERITAS-PRO) at baseline and follow-up. A scheduled interim analysis (30% of patients recruited) was conducted with data collected up to 2 July 2018. RESULTS: At the cut-off, 160 enrolled patients were included in the baseline analysis set, of whom 89 had ≥ 6 months of follow-up data available (median observation period 201 days), 33% of whom had completed one year of the study. Median (range) patient age was 22 (2‒69) years, time since diagnosis was 15 (0.5‒64) years, and most patients (76/89, 85%) had baseline FVIII level of <1%. Treatment assignments are shown in the table. All patients had received pre-study prophylaxis, for a median of 15 years, with 66% of patients using rFVIII-FS as their most recent FVIII treatment prior to BAY 81-8973. Most (91%) had been treated with BAY 81-8973 for <3 months prior to study entry. Pre-study, 72% of patients were treated ≥3 times per week (xW). At baseline, most patients (59%) were assigned treatment ≥3xW (every day, 1%; every other day, 16%; 3xW, 41%). The majority remained on their previous regimen (78% on ≤2xW and 97% on ≥3xW); any changes were mainly a reduction in frequency on BAY 81-8973 vs previous treatment (22%), with only 2% increasing frequency on BAY 81-8973. At last follow up, most patients remained on the same regimen: 60% on ≥3xW (≥ every other day, 17%; 3xW, 42%). Most patients (92%) did not alter their dosing frequency. Of the 8% who changed dosing frequency, the majority (6 patients) changed from ≥3xW to ≤2xW; 1 patient changed from ≤2xW to ≥3xW. The median prescribed weekly dose was 52 IU/kg (64 IU/kg for ≥3xW and 43 IU/kg for ≤2xW) on study, slightly lower than those with previous product: 56 IU/Kg overall, 64 IU/kg for ≥3xW and 50 IU/kg for ≤2xW. Median (Q1; Q3) patient diary-reported annualized joint bleed rates were 1.5 (0.0; 5.3), 1.2 (0.0; 5.3) and 1.4 (0.0; 6.1); for ≤2xW, ≥3xW, and all patients, respectively. HEMO-SAT and VERITAS-PRO data will be presented in the poster. No recruited patients developed inhibitors with BAY 81-8973. CONCLUSIONS: These real-world data from 89 patients show that the range of dosing options available for BAY 81-8973 allowed the majority of patients to become established quickly on this treatment upon switching. In the few instances where patients changed dosing frequency either upon switching to BAY 81-8973 or once established on treatment, most moved to less frequent treatment. Joint bleeding rates confirm and extend findings from the clinical trials and speak to effective bleeding prophylaxis with BAY 81-8973 in a real-world setting. Therefore, BAY 81-8973 treatment may be successfully individualized according to patient need and disease characteristics. Disclosures Wang: Terumo BCT: Other: CPC Clinical Research; CSL Behring: Consultancy; Bayer, Bioverative, Novo Nordisk, Octapharma, Shire, Genentech, Biomarain, Pfizer, CSL Behring, HEMA Biologics, Daiichi Sankyo: Research Funding; Bayer: Consultancy; Bayer, Novo Nordisk, Octapharma, Genentech, HEMA Biologics, Shire, CSL Behring: Honoraria; Novo Nordisk: Consultancy. Maes:Bayer: Honoraria. Rauchensteiner:Bayer: Employment.

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Augmenting the Accuracy of Trainee Doctors in Diagnosing Skin Neoplasms in a Real-World Setting: A Prospective Before and After Study (Preprint)

10.2196/preprints.26023 ◽

2020 ◽

Author(s):

Seung Seog Han ◽

Young Jae Kim ◽

Chong Hyun Won ◽

Mi Woo Lee ◽

Jung-Won Shin ◽

...

Keyword(s):

Artificial Intelligence ◽

Real World ◽

Tertiary Care ◽

Skin Neoplasms ◽

Differential Diagnoses ◽

Control Group ◽

Routine Examination ◽

Real World Setting ◽

Before And After ◽

The Difference

BACKGROUND Although deep neural networks have shown promising results in diagnosing skin cancer, a prospective evaluation in a real-world setting could confirm these results. OBJECTIVE The aim of this study was to evaluate whether an algorithm (http://b2019.modelderm.com) could improve the accuracy of nondermatologists in diagnosing skin neoplasms. METHODS A total of 285 cases (random series) with skin neoplasms suspected by either physicians or patients were recruited in two tertiary care centers located in South Korea. An artificial intelligence (AI) group (144 cases, mean [SD] age, 57.0 [17.7] years; 62 [43.1%] men) was diagnosed via routine examination with capturing photographs and assisted by the algorithm, whereas the control group (141 cases, mean [SD] age, 61.0 [15.3] years; 52 [36.9%] men) was diagnosed only via routine examination with a photographic review. The accuracy of the nondermatologists before and after the interventions was compared. RESULTS Among the AI group, the accuracy of the first impression (Top-1 accuracy; 58.3%) after the assistance was higher than that before the assistance (46.5%, P = 0.0081). The number of differential diagnoses of the participants increased from 1.9 ± 0.5 to 2.2 ± 0.6 after the assistance (P < 0.0001). In the control group, the difference in the Top-1 accuracy between before and after reviewing photographs was not significant (before, 46.1%; after, 51.8%; P = 0.1867) and the number of differential diagnoses was not also significantly increased (before, 2.0 ± 0.4; after, 2.1 ± 0.5; P = 0.5653). CONCLUSIONS In real-world settings, artificial intelligence augmented the diagnostic accuracy of trainee doctors. The limitation of this study is that the algorithm was tested only for Asians recruited from a single region. Additional international randomized controlled trials involving various ethnicities are required.

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Effectiveness and Safety Outcomes in Patients with Hemophilia a Receiving Antihemophilic Factor (Recombinant) for at Least 5 Years in a Real-World Setting: 6-Year Interim Analysis of the Ahead International and German Studies

Blood ◽

10.1182/blood-2020-139873 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Dimitrios A. Tsakiris ◽

Johannes Oldenburg ◽

Robert Klamroth ◽

Benoît Guillet ◽

Kate Khair ◽

...

Keyword(s):

Clinical Practice ◽

Real World ◽

Interim Analysis ◽

Research Funding ◽

Hemophilia A ◽

Routine Clinical Practice ◽

Publicly Traded ◽

Real World Setting ◽

Antihemophilic Factor

Introduction: Long-term effectiveness and safety data in patients treated in routine clinical practice settings can be captured from real-world studies. The international (INT) and German (GER) Antihemophilic factor (recombinant; rAHF) Hemophilia A (HA) outcome Database (AHEAD) studies assess long-term effectiveness and safety outcomes in patients with moderate HA (factor VIII level 1-5%) or severe HA (factor VIII <1%) receiving rAHF (ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in routine clinical practice. Methods: These are non-interventional, prospective, long-term, multicenter studies (INT: NCT02078427; GER: DRKS 00000556). Key outcomes include Gilbert scores (primary endpoint; pain scored 0-3; bleeding scored 0-3, and physical exam scored 0-12), annualized bleeding rates (ABRs) by disease severity, and adverse events (AEs). Findings reported here are from the 6-year interim analysis (data cut-off: July 15, 2019), and focus on patients who have received rAHF prophylaxis or on-demand (OD) treatment for ≥5 years in the studies. All data are reported for the safety analysis set (SAS), which comprised patients who passed screening and were assigned to a treatment group or regimen in the INT study, or were enrolled and have received ≥1 dose of rAHF since study enrollment in the GER study. Results: At the time of analysis, the INT study SAS comprised 707 patients, 156 of whom had received ≥5 years of rAHF treatment during the study. The GER study SAS comprised 382 patients, 231 of whom had received ≥5 years of rAHF treatment. Average Gilbert scores (all joints) were consistently low (years 1-6: median 0-1.0; mean 0-1.3) for both children aged 2 to <12 years and adolescents aged 12 to <18 years receiving rAHF prophylaxis within both studies. In the INT study, average Gilbert scores were lower with prophylaxis than with OD therapy in adults (aged ≥18 years) throughout the observation period (years 1-6: median: 0.9-1.4 [n=8-25] vs 1.4-6.3 [n=2-8], respectively; mean: 1.4-2.2 vs 2.1-6.3; respectively); significant differences (P<0.05) between mean values were observed for years 3, 4, and 6. In the GER study, average Gilbert scores were slightly higher with prophylaxis than with OD in adults (years 1-6: median: 0.7-2.2 [n=12-37] vs 0.3-1.4 [n=2-15], respectively; mean: 1.0-2.7 vs 0.5-2.2, respectively; P-values not available). In the INT study, ABRs were consistently lower in patients receiving rAHF prophylaxis than in those receiving rAHF OD, irrespective of disease severity (Table). A similar trend was observed in the GER study in patients with severe HA, whereas ABRs were similar for both treatment regimens in patients with moderate HA. In both studies, greater proportions of patients with moderate or severe HA receiving rAHF prophylaxis had 0 bleeds than those receiving rAHF OD (Table). In the INT study, 842 AEs were reported in 116/156 (74.4%) patients, including 2 treatment-related serious AEs in 2 (1.3%) patients. In the GER study, 1321 AEs were reported in 197/231 (85.3%) patients, including 29 treatment-related serious AEs in 14 (6.1%) patients. Conclusions: These findings in patients receiving rAHF for ≥5 years in a real-world setting corroborate previous data on the long-term efficacy and tolerability of rAHF in patients with moderate or severe HA. rAHF demonstrated effectiveness in maintaining joint health (as measured by Gilbert scores) in adult patients. Table Disclosures Tsakiris: Roche: Research Funding; Shire, a Takeda company: Research Funding; Sobi: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Octapharma: Research Funding. Oldenburg:Sobi: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Biotest: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; Chugai: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Klamroth:Pfizer: Consultancy, Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Grifols: Speakers Bureau; Takeda/Shire: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Biomarin: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau. Guillet:CSL Behring: Research Funding, Speakers Bureau; Octapharma: Research Funding; Bayer: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Shire, a Takeda company: Consultancy, Speakers Bureau; Roche-Chugai: Consultancy, Speakers Bureau. Khair:Shire, a Takeda company: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Baxalta/Shire, Takeda companies: Research Funding. Huth-Kühne:Bayer: Consultancy; CSL Behring: Consultancy; Shire, a Takeda company: Consultancy; Sobi: Consultancy. Kurnik:Sobi: Consultancy, Research Funding; Biotest: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau. Regensburger:Takeda Pharma Vertrieb GmbH & Co. KG: Current Employment, Current equity holder in publicly-traded company. Botha:Takeda Pharmaceutical International AG: Current Employment, Current equity holder in publicly-traded company. Fernandez:Takeda Pharmaceutical International AG: Current Employment, Current equity holder in publicly-traded company. Tang:Takeda Pharmaceutical International AG: Current Employment, Current equity holder in publicly-traded company. Ozelo:Pfizer: Consultancy, Research Funding; Shire/Takeda: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Bioverativ/Sanofi: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau.

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