Abstract: The Hemophilia Experiences, Results and Opportunities (HERO) initiative assessed psychosocial issues reported by people with moderate to severe hemophilia and was led by a multidisciplinary international advisory board. This analysis reports data from young adult respondents (aged 18–30 years), including both US and overall global (including US respondents) results, and investigates treatment outcomes, quality of life, and impacts of hemophilia on relationships. More young adults in HERO received prophylaxis than on‐demand treatment, although a majority reported not using factor products exactly as prescribed, and 50% of global respondents and 26% of US respondents reported issues with access to factor replacement therapy in the previous 5 years. Many young adults with hemophilia reported comorbidities, including bone/skeletal arthritis, chronic pain, and viral infections, and nearly half of young adults reported anxiety/depression. Most reported pain interference with daily activities in the past 4 weeks, although a majority reported participating in lower‐risk activities and approximately half in intermediate‐risk activities. Most young adults were very or quite satisfied with the support of partners/spouses, family, and friends, although roughly one‐third reported that hemophilia affected their ability to develop close relationships with a partner. A majority of young adults reported that hemophilia has had a negative impact on employment, and 62% of global respondents and 78% of US respondents were employed at least part‐time. Together these data highlight the psychosocial issues experienced by young adults with hemophilia and suggest that increased focus on these issues may improve comprehensive care during the transition to adulthood. Am. J. Hematol. 90:S3–S10, 2015. © 2015 Wiley Periodicals, Inc.

Abstract: INTRODUCTION: Patients with GT, a rare congenital platelet disorder due to ­an abnormality of glycoprotein IIb/IIIa expression, experience frequent and severe mucocutaneous bleeding. Little is known about how and where US GT patients receive care, or about its impact on patients and their families. This first survey is aimed to capture their experience and perspectives. METHODS: A web-based structured quantitative survey (~45 min) was distributed in 1Q 2014 to adult patients (≥18 years old) and parents of affected children ( 〈 18 years) in the US using the Glanzmann’s Research Foundation mailing list and Facebook® page. Results are reported as mean (median) unless noted. RESULTS: Respondents included 14 adults with GT (mean age 39.3 years, range 19-55, 86% female) and 9 parents (mean age 42.1 years, range 29-54, 89% female) of children with GT (mean age 9.3 years, range 1-17, 33% female). Respondents had post-high school education (92%), were employed (65%) or students (13%), and had health insurance (87%). Age at diagnosis was 6.2 (2) years and was higher for adults (9.3 [5]) than children (1.7 [0.5] ). Frequent presenting symptoms were skin bleeding/bruising (83%), gum/mouth/tooth bleeding (46%), epistaxis (58%), and abnormal menstrual cycles (21%). Time from first bleed to hematology referral was 23 (5) months (38% 〈 3 months); most patients were referred by pediatricians (54%) or internists/family practitioners (21%). Time from first bleed to definitive diagnosis was 33 (13) months (21% 〈 3 months). Parents reported slightly shorter times for both. Confirmatory testing was most often in the hematologists’ lab (58%) or hospital/ER (38%). Treatment team included hemophilia treatment center (HTC)-based hematologist (50%), non-HTC hematologist/oncologist (41%), pediatrician (38%), OB/GYN (33%), internist (25%) and ENT (17%). Most bleeds required none (59%) or local (25%) treatment. Nearly all patients (83%) received a transfusion at some point (67% blood; 75% platelets); 70% received it at a hospital near home. Most patients (78%) reported platelet transfusions controlled bleeds in the past; 56% reported platelet transfusions controlled bleeds currently. Nearly half (44%) were told they were “refractory”; 50% were told they were tested for antibodies and of those tested, 56% were told they had “antibodies” to platelets. Median perceived disease control (0-10 scale, 10=very well controlled) was 6.83 (adults 6.33, parents 7.67). Most adults (93%) and majority of children (67%) found GT impacted school, with issues including absence, bullying, and falling behind. Both adults (87%) and children (78%) reported GT impacted participation in activities/sports in childhood due to restrictions, triggered bleeds, and embarrassment. Half of the adult patients reported still being impacted with activities. GT also impacted relationships with friends and peers for children (56%) and adults (40% during childhood, 20% currently); issues included being teased, marginalized, and called “abused” due to constant bruising. Parents reported having a child with GT impacted their (44%) or their spouses (22%) employment, including frequent absences resulting in reprimands and terminations; 27% of adults reported impacts on employment including fatigue, bleeds, and lost work days. Most respondents were very/quite satisfied with support of spouses (79%), family (76%), and friends (83%), but less so with support of schools (56%) and employers (50%). Hematologists (91%) and websites (91%) were the most common sources of information. Most useful (1-5, 5=most useful) sources of information were other patients (5), other caregivers (5), nurses (4.2), hematologists (4.1), websites (4.1) and national organizations (3.6). Many noted major consumer organizations related to the bleeding disorders population have little or no information on GT. Looking to the future, adults and parents desired increased education of the medical community, more immediate treatment in the ER, focus on pre-activity treatment to prevent bleeding, and improved coordination of care. CONCLUSION: While limited in scope, these data provide directional insight into the burden of living with or caring for one or more children with GT. In particular, the psychosocial impact of frequent mucocutaneous bleeding in childhood deserves further study. These results highlight the need for better resources for families and healthcare providers. Disclosures Cooper: Novo Nordisk: Employment.

Abstract: Bleeding in hemophilia is believed to transition from more traumatic etiologies in early childhood to spontaneous bleeding in adolescents and adults as target joints develop and arthropathy progresses. The HERO study examined psychosocial issues impacting adults and children (and their parents) with moderate-severe hemophilia. As part of HERO, adults/parents reported bleed frequency/location, most affected joint, causes of bleeding, and current employment/activities. Prior analyses highlighted differences in bleed frequency by treatment regimen and age, prompting further exploration of potential causes of bleeding. Methods People with hemophilia (PWH) (≥18 years) and parents of children with hemophilia ( 〈 18 years) (CWH) were recruited in 10 countries. In the US, subjects were recruited online through the National Hemophilia Foundation's Facebook page and eNotes. Following informed consent, adults/parents completed distinct surveys (∼ 45 min). Results The 189 US PWH had a median (range) age of 35 (18-74). The 190 US parents of children with hemophilia had a median (range) age of 37 (23-59) years. The mean age of the oldest son 〈 18 years was 8.7 years. Most PWH/parents reported hemophilia A (59%/66%) with (24%/9%) reporting inhibitors. Most parent respondents were female (79%) and were responsible for their son's care (75%). PWH on likely secondary prophylaxis (PPX) reported higher overall median number of hemorrhages requiring treatment in the prior 12 months compared to those treated on demand (OD); there was little difference seen across employment and age (see table). More unemployed PWH reported a specific joint affected by hemorrhages. The ankle was the most frequently cited affected joint. Repetitive activity was reported as the most common cause of the most recent hemorrhage in those who used PPX and was more common in those working (40%) compared to those unemployed (22%). Spontaneous bleeding was most common in those unemployed (46%) and aged ≥41 years (41%). PWH reported more success in following HTC recommendations around taking medications than exercise. Parents of CWH on PPX reported fewer hemorrhages than those treated OD, particularly due to differences in hemarthroses (see table). Older children were reported to have more frequent joint and muscle bleeding. A specific joint impacted by hemorrhage was reported more frequently in older compared to younger CWH (57 vs 44%); all groups except inhibitors reported trauma and repetitive activities combined as the most common causes of the last hemorrhage. The knee/elbow was the most commonly reported specific joint in the age 0-6 years group and the ankle in the age 7-17 years group. Parents generally reported good success in following HTC recommendations. Conclusions HERO provides unique insight into the causes of bleeding in PWH and CWH. The addition of a category of “repetitive activity” in the HERO study to reflect non-traumatic repetitive work/school/sports activity suggests there might be triggers for bleeding previously described as “spontaneous”. This observation warrants further attention by the HTC team including the physiotherapist, and should be investigated in prospective observational studies. Disclosures: Valentino: Baxter Bioscience, Bayer Healthcare, Biogen, CSL Behring, GTC Biotherapeutics, Inspiration: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Forsyth:Novo Nordisk: Consultancy. Witkop:Novo Nordisk: Consultancy. Guelcher:Novo Nordisk: Consultancy. Lambing:Novo Nordisk: Consultancy. Cooper:Novo Nordisk Inc.: Employment.

Abstract: Introduction: With many standard half-life (SHL) and extended half-life (EHL) recombinant factor VIII and factor IX products licensed in the US over the last 6 years, it is likely that previously treated patients (PTPs) will consider switching to a new EHL FVIII or FIX product. Although past product switching surveillance suggests no increased inhibitor development risk, there is the need for a real-world data on the incidence of inhibitor development following switching from SHL to EHL rFVIII or rFIX in PTPs with hemophilia A and B. Methods: A longitudinal, observational study of participants with Hemophilia A or B who switched to a rFVIII or rFIX concentrate licensed after Jan 1, 2013. The study included retrospective (switched within 50 exposure days (EDs) and prospective arms. Participants were recruited from ATHN-affiliated Hemophilia Treatment Centers (HTCs). The primary outcome measure was the development of a new inhibitor (i.e. neutralizing antibodies to factor VIII or IX) a 1 year or during the 50 EDs following the product switch. Plasma samples were collected at baseline, 10 EDs and 50 EDs. Inclusion criteria include moderate or severe hemophilia A/B currently on a plasma-derived or recombinant FVIII or FIX concentrate with planned or recent switch to an EHL FVIII or FIX concentrate approved after Jan 1, 2013. Participants with an active inhibitor at time of enrollment or undergoing ITI or switched to a non-factor product were excluded. Results: 303 hemophilia participants from 27 treatment centers were enrolled from 2015 to June 2019. The median age at enrollment was 17 years (IQR 10-32 years). 300 of 303 participants were male, Caucasian (72.6%) and had private insurance (44.9%). 74.3% were FVIII deficient and 25.7% were FIX deficient. Most had severe hemophilia A or B, 82.3% (n=237) and 12.8% (n=37) had a prior history of inhibitor but were negative at the time of enrollment. Prior to the switching, 92.1% (n=197) and 7.9% (n=17) of hemophilia A participants took standard rFVIII or pdFVIII respectively, while 87.8% (n=65) and 12.2% (n=9) of hemophilia B participants took standard rFIX or pdFIX, respectively. The three most frequent switching reasons were extended half-life consideration (n=192; 66.7%), a desire for a longer acting version (n=55; 19.1%) and less than expected clinical response to the current product (n=15; 5.2%). Among 214 participants with hemophilia A, 182 (85.0%) switched to FVIII EHL products while 23 (10.7%) switched to new SHL FVIII. For nine patients (4.2%) switching product information was not available. 72 out of 74 (97.3%) participants with hemophilia B that switched products, switched to an EHL rFIX. Eleven hemophilia participants (six A and five B) entered a second cycle of switching after the completion of the first switching cycle. Following that, four switched to FVIII EHL products, two to new SHL rFVIII and five to rFIX EHL products. A total of 193 (63.7%; 148 FVIII, 45 FIX) participants completed the clinical trial while 36 (11.9%; 26 FVIII, 10 FIX) did not complete the trial and 74 (24.4%) are ongoing in the trial. None of 303 (0%) enrolled participants developed an inhibitor, the primary outcome for this study, through data updated 6/2019. Variability was noted in per-site enrollment. The median enrollment per Hemophilia Treatment Center (HTC) was 10, the IQR was 7-16 with a range of 1-31. The types of factors associated with patients switches are summarized in the figure. Conclusion: No new inhibitors were noted among 303 moderate/severe hemophilia A/B PTPs without active inhibitors at entry, who switched factor VIII or IX products over 50 exposure days or 12 months. This result provides real-world evidence of the rarity of inhibitor development after a product switch in PTPs. The study also achieved a key logistical objective: to demonstrate feasibility of a prospective observational study across ATHN sites. Figure Legend: Factor types to which ATHN-2 patients switched during the study. Disclosures Sidonio: Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: 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, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guelcher:Takeda: Other: Advisory Board; Genetech: Other: Advisory Board; NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board. Takemoto:genentech: Membership on an entity's Board of Directors or advisory committees; novartis: Other: DSMB membership. Tarantino:Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Magellan Healthcare: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial PI, Speakers Bureau; Roche: Consultancy; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Grant Reviewer , Research Funding; Octapharma: Consultancy, Speakers Bureau. Neufeld:Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored).

Abstract: Health‐related quality of life ( HRQ oL) is impaired in patients with hemophilia; however, the impact in mild/moderate hemophilia B and affected women is not well characterized. Objective To evaluate factors that affect HRQ oL in adults with hemophilia B and caregivers of affected children. Methods US adult patients and caregivers of affected children completed distinct ~1‐hour online surveys including patient‐reported outcome instruments. Results In total, 299 adult patients and 150 caregivers participated. Adults with moderate hemophilia reported poorer health status (median EQ ‐5D‐5L index score, 0.63) than those with mild (0.73) or severe (0.74) hemophilia. Women reported greater pain severity than men on the Brief Pain Inventory v2 Short Form (median, 7.00 vs 5.00). Based on the Patient Health Questionnaire, mild or worse depression was observed in 〉 50% of adult respondents, and depression was reported more often in those with moderate and severe hemophilia vs those with mild hemophilia. Most caregivers reported at least mild depression. Conclusion Pain, functional impairment, and depression/anxiety are present at higher‐than‐expected levels in individuals with hemophilia B. The large proportion of individuals with mild/moderate hemophilia and women with reduced health status suggests significant unmet needs in this population.

Abstract: FV is primarily produced in the liver, and congenital FV deficiency is a disorder with an incidence of one in 1 million. Standard care is to treat severe bleeding phenotypes with FFP as there is no recombinant or plasma‐derived FV concentrate. We present a case of a neonate with known severe FV deficiency diagnosed after prolonged bleeding after circumcision who represented at age 2 months with a large left intraparenchymal hemorrhage. His bleed was treated with FFP , platelet transfusion, recombinant VII a, and emergent evacuation. He was maintained on plasma infusions but was unable to space his infusions beyond 48 hours. Liver transplantation was considered as a definitive treatment for this condition. While awaiting a suitable liver, his FV trough levels occasionally dropped below 5%, and he suffered from a second acute intracranial bleed. He received an orthotopic liver transplant at age 5 months, resulting in correction of his FV levels. He has not required any plasma infusions post‐transplantation and has had no further bleeding episodes. Liver transplantation should be considered as definitive treatment early in the course for patients with severe FV deficiency and first time life‐threatening bleed.

Abstract: Introduction Emicizumab is a recombinant humanized monoclonal antibody that bridges factor IXa and Factor Xa and is administered via subcutaneous injection. After initial FDA approval for patients with hemophilia A (HA) and inhibitors, it was approved in October 2018 for prophylaxis in patients with HA without inhibitors of all ages. In clinical trials of subjects without inhibitors, emicizumab was studied only in those 〉 12 years of age. The primary objective of this study was to report our "real-world", post-licensure experience with emicizumab across a more heterogenous patient population, comparing annualized bleeding rates prior to and after initiating emicizumab. Secondary objectives included evaluating for serious adverse events including death, thrombosis or drug discontinuation. Methods We conducted a multi-center observational study at 3 federally funded Hemophilia Treatment Centers: Children's Hospital of Philadelphia, Virginia Commonwealth University and Children's National Health System. Inclusion criteria included patients with HA initiated on emicizumab prior to May 15th 2019. Data extraction included: demographics, diagnosis, prior HA history (inhibitor, prophylaxis treatment regimen), emicizumab dosing data, bleeding events (all bleeds, treated bleeds, joint bleeds, traumatic bleeds) and thrombotic events from the 6 months prior to emicizumab until July 15th 2019. Annualized bleeding rates (ABR) were calculated to account for variable follow up. Wilcoxon Sign-Rank Difference Test was used to test the difference in number of bleeds and McNemar's test was used to test the difference in proportions of patients with ABR=0. Results Ninety-two patients met inclusion criteria: 89 male and 89 with severe HA (3 moderate HA) (Table 1). Age at initiation of emicizumab ranged from 5 weeks to 55 years; median 8.6 yrs (IQR 4.8-13.5 yrs). Nineteen patients had an active inhibitor at the time of starting emicizumab; the remaining 73 did not have an inhibitor, and most (86%) were on prophylaxis prior to emicizumab. Sixty-two patients were 〈 12 years of age (13 with inhibitors). Median duration of emicizumab therapy was 48 weeks (inhibitors) and 22 weeks (non-inhibitors), with a total follow up of 53.3 patient years. In patients with inhibitors, the ABR (treated bleeds) prior to emicizumab was 6.2 events (95% CI, 0.98 to 11.4) compared to 0.3 events (95% CI, 0 to 0.73) on emicizumab, p=0.002. In subjects without inhibitors, the ABR prior to emicizumab was 1.8 events (95% CI, 0.66 to 2.96) compared to 0.22 events (95% CI, 0.05 to 0.39) on emicizumab, p 〈 0.001. Additional data on bleeding events is provided in Table 1. The proportion of patients with ABR=0 increased in both inhibitor (from 46% to 74%, p=0.06) and non-inhibitor subjects (from 60 to 78%, p=0.015). All patients received 1.5 mg/kg weekly x 4 loading doses, followed by either weekly (27%), every other week (70%), or monthly (3%) dosing; patients with inhibitors were more likely to receive weekly dosing. No patients who initiated emicizumab discontinued the drug or developed a neutralizing antibody to FVIII or emicizumab, although patients have not been consistently screened for these antibodies. No thrombotic or thrombotic microangiopathy events or death have occurred. Conclusions Our favorable clinical experience with emicizumab post-licensure in patients with HA is similar to that reported in the clinical trials. Although excluded from the clinical trials, patients with HA without inhibitors 〈 12 years accounted for the majority (67%) of our cohort. As anticipated, these younger patients appear to experience the same benefit as patients 〉 12. No serious drug-related adverse events were reported, although the overall study period is relatively short. Ongoing follow up of these patients, and others, will be important to assess the ongoing safety and efficacy profile of this novel therapy. Updated data on this cohort will be presented at the ASH meeting Disclosures Guelcher: NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board; Takeda: Other: Advisory Board; Genetech: Other: Advisory Board. Butler:pfizer: Other: Advisory board; Hema-Biologics: Consultancy; genetech: Other: Advisory board. Guerrera:Genetech: Other: Advisory Board; Kendrion: Other: Advisory Board; Shire: Other: Advisory Board; Bayer: Other: Advisory Board; Bioverativ: Consultancy; Pfizer: Other: Advisory Board; Novo Nordisk: Consultancy. Raffini:Roche: Other: Advisory Board; Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board.

Abstract: The management of patients with haemophilia is complex and requires lifelong care to be delivered by a specialist multidisciplinary team. Haemophilia B results from a deficiency or absence in coagulation factor IX (FIX), leading to easy bruising, and musculoskeletal and internal bleeding. For patients with severe or moderate haemophilia B, prophylaxis with standard half-life (SHL) coagulation FIX products requires frequent intravenous administration, which may negatively impact treatment adherence and increase burden of care. A recombinant fusion protein linking recombinant FIX (rFIX) with recombinant human albumin, rIX-FP, has an extended half-life compared with SHL rFIX, and has demonstrated a favourable safety and efficacy profile for the prevention and treatment of bleeding episodes in phase III and real-world studies of patients with severe haemophilia B. rIX-FP enables treatment to be tailored to the needs of individual patients, with dosing flexibility allowing selected patients to be treated with prophylaxis dosing intervals of 7, 10, 14 or 21 days. Patients switching to rIX-FP can reduce their annualised bleeding rate and some have successfully reduced their prophylactic dosing frequency while maintaining low bleeding rates and consistent factor consumption. This may ultimately minimise the occurrence of haemophilic arthropathy and improve patient quality of life. Educating patients and caregivers on the sustained use of rIX-FP prophylaxis is essential. The lifelong support and guidance provided by healthcare professionals at haemophilia treatment centres (HTCs) are critical for providing an optimal treatment approach that can increase adherence to treatment. This article reviews the pharmacokinetics, efficacy, and safety of rIX-FP demonstrated in clinical trials and clinical practice, and discusses haemophilia nurses’ clinical experiences with rIX-FP in patients in their HTCs.