ALBERT

Description: Background: Hemophilia-A is a chronic inherited bleeding disorder that results from deficiencies in factor VIII. Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care. However, about 20-30% of patients with severe hemophilia A may develop neutralizing antibodies (inhibitors) against the coagulation factor VIII. The Immune Tolerance Induction (ITI) method, consist in the regular infusion of variable FVIII doses to induce FVIII antigen-specific tolerance. It has proven the most effective inhibitor eradication treatment in patients with high-titer inhibitors. Current published studies reported wide range of findings on the factor usage and cost of treatment. The objective of this study is to describe the consumption, duration, and cost of ITI treatment in US healthcare settings. Methods: This retrospective analysis used MarketScan, an US health insurance claim database from January 2010 to September 2015. Eligible patients were: male hemophilia-A inhibitor patients who received ITI treatment. ITI treatment was identified as patients who tested Bethesda/Nijmegen assays between 30 days prior to an ITI index date and the end of study period; and used high dose of factor therapy (〉3 times of the median IU factors dispensed for patients in the same age group for more than 5 consecutive months, allowing one month gap). Conclusion of ITI treatment was defined as when the amount of IU dispensed has fallen under 1.5 times of the median amount dispensed, or remaining in ITI treatment at the end of study period. Patients, who used by-pass agents to treat bleeding without undergoing ITI, were excluded. The total cost of ITI treatment was focused only on the cost of factor therapy. The treatment duration, cost, and IU consumption were further stratified by age groups and specific factor therapies. Results: Of the 2,302 hemophilia-A patients, 231 inhibitor patients were identified. A total of 72 patients used high dose short-acting factors for ITI treatment. No patient receiving long-acting factor was captured in the inhibitor population. Table 1 lists the patient counts, duration and cost of ITI treatment by age groups. Higher percentages of younger patient groups developed inhibitor compared with older age groups. About 14% of hemophilia-A patients aged 7 and under had ITI treatment. The older groups (aged 16 and older) had higher total costs as they required higher IU of factor therapy. The average duration of ITI treatment was 18.7 months, and the average total cost was $1,463,668 per patient regardless of the type of short acting factor therapy used. Conclusions: This US health insurance claim database study reflects that the current utilization of short acting factor for ITI treatment is associated with high cost burden. Products that decrease or eliminate inhibitor formation should be developed. Disclosures Su: Novartis Pharmaceuticals Corporation: Employment; Biogen: Employment, Equity Ownership. Zhou:Biogen: Employment, Equity Ownership. Buckley:Biogen: Employment, Equity Ownership. Rising:Biogen: Employment, Equity Ownership. Hou:Biogen: Employment, Equity Ownership. Jain:Biogen: Employment, Equity Ownership.

Description: Introduction: The treatment landscape for hemophilia A has evolved since the introduction of extended half-life (EHL) factor/non-factor VIII products, which allows for treatment personalization as per individual need, such as a less frequent infusion schedule and increased protection. Many different treatment attributes (e.g. safety, efficacy, and treatment burden) can influence patients' and caregivers' decisions in their choice of treatment. We used a discrete choice experiment (DCE) to elicit preferences from hemophilia A patients and caregivers for the treatment attributes of new EHL/non-factor products. Methods: Adult patients and caregivers providing care for a young patient (

Description: Introduction: Recombinant factor IX Fc fusion protein (rFIXFc) was the first extended half-life FIX product approved in the United States to treat children and adults with hemophilia B. Long-term data from clinical trials have demonstrated the safety and efficacy of rFIXFc as well as an extended dosing interval (once weekly or every 10‒14 days based on individual needs); however, real-world data are limited (Wang et al. Haemophilia, 2018; Buckley et al. AMCP NEXUS, 2015). We therefore performed a retrospective chart review to further understand the clinical experience and outcomes associated with real-world treatment of hemophilia B with rFIXFc. Methods: This retrospective chart review is being conducted at 6 sites across different regions of the United States and aims to include 70 patient charts. Data entry for 43 patient charts has been completed to date (cutoff: June 29, 2018). Data collection is ongoing. Inclusion criteria were diagnosis of hemophilia B and receipt of rFIXFc for ≥6 months. Subjects with other coagulation disorders or any record of positive FIX inhibitor titers were excluded. De-identified subject-level data were transcribed onto anonymous electronic case report forms. Endpoints included changes in FIX therapy dosing interval, factor consumption, bleed control, and patient adherence before and after rFIXFc initiation. Descriptive statistics were used to summarize the results. Results: For the 43 charts available for analysis, the duration of follow-up receiving rFIXFc ranged from 0.5 to 3.7 years. Of these, 58% of subjects (25/43) were 〉18 years of age, 77% (33/43) were of white race, and 51% (22/43) had severe hemophilia B (Table 1). The most common genotype was missense, occurring in 63% of subjects (27/43). Among subjects with comorbidity, 37% reported hemophilic arthropathy (16/43) and 28% had hepatitis C (12/43). All 22 subjects with severe hemophilia B were treated with rFIXFc prophylactically compared with 9/15 moderate and 3/6 mild cases. From the data collected thus far, 94% of prophylaxis subjects were on a dosing interval of weekly or longer (every 7 days, n=20; every 10 days, n=3; and every 14 days, n=9). The total weekly dose before and after switching to rFIXFc prophylaxis were available for 20 subjects. Of the 12 adults (9 severe, 2 moderate, and 1 mild), the median weekly factor consumption decreased from 111 IU/kg to 52.5 IU/kg. A similar pattern was observed for subjects who were 12-18 years of age (n=4). For subjects

Description: Introduction: The completed Phase 3 A-LONG (NCT01181128) and Kids A-LONG (NCT01458106) studies established the safety and efficacy of rFVIIIFc among adults/adolescents and children with severe hemophilia A, respectively. Long-term safety and efficacy of rFVIIIFc are being evaluated in the ongoing ASPIRE extension study (NCT01454739). For people with hemophilia, frequent bleeding into the same joint (a target joint) may contribute to hemophilic arthropathy (chronic joint disease). Here we report longitudinal data from subjects with target joints at entry into A-LONG and Kids A-LONG throughout ASPIRE. Methods: Subjects with ≥1 target joint (major joint with ≥3 bleeding episodes in a 6-mo period) at entry into the parent study (A-LONG or Kids A-LONG) with available prestudy (pre-parent study) and on-study data were evaluated. There are 4 treatment groups in ASPIRE for subjects ≥12 y: individualized prophylaxis (IP), weekly prophylaxis (WP), modified prophylaxis (MP; for subjects not achieving optimal prophylaxis, as intended by treating physician, with IP or WP), or episodic treatment. Subjects

Description: Introduction Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia (AIHA) accounting for 20% of all cases, with no approved therapies and limited management options for patients. CAD is characterized by immunoglobulin M-mediated erythrocyte agglutination, which triggers activation of the classical complement pathway leading to hemolysis and subsequent anemia. Red blood cell (RBC) transfusions are used as a supportive treatment in CAD to temporarily alleviate anemia, although the transfusion practices are variable among providers treating patients with CAD. Recent RBC transfusion guidelines from the AABB (formerly the American Association of Blood Banks) recommend that transfusions be administered with a restrictive threshold in most clinical scenarios (ie, transfusion is not indicated until hemoglobin [Hb] reaches 7-8 g/dL and/or patients exhibit anemia-related symptoms) to avoid associated complications such as acute reactions, alloantibody development, and hemochromatosis (Carson et al, JAMA, 2016; Carson et al, N Engl J Med, 2017). Because of the dearth of information available regarding trends in RBC transfusion practices among US hematologists, the objective of this longitudinal, retrospective, observational assessment of an electronic medical record database was to evaluate transfusion practices applied to patients with CAD in the US. Methods Patients were retrospectively identified from Optum® de-identified Electronic Health Record (EHR) dataset. Adult patients with ≥1 AIHA-related medical encounter between January 2007 and September 2018 (study period) and ≥3 mentions of CAD-related terms from physician notes ("cold agglutinin disease," "cold autoimmune hemolytic anemia," or "cold agglutinin hemoglobinuria") were included (Broome et al, Blood, 2017). The index date for each patient was the date of first mention of CAD during the study period. The baseline period was defined as the interval from the start of medical activity in the EHR database or study period (whichever occurred later) to the index date, and the follow-up period was defined as the interval from the index date to the end of the study period, end of medical activity, or death (whichever occurred earlier). The study sample was categorized into 2 study groups, the transfusion group (patients with CAD with ≥1 RBC transfusion after the index date) and the non-transfusion group (patients with CAD without any transfusions during the study period). Patients were further grouped based on the following Hb levels (g/dL): 10 to ≤12. The closest Hb level prior to the most recent transfusion (within the prior 15 days and the lowest level) was used for the transfusion group and the lowest Hb level during the study period was used for the non-transfusion group. Descriptive statistics included mean, standard deviation, and median values for continuous variables and frequency (n and percent) for categorical variables. No adjustment was made for this descriptive analysis. Results A total of 903 patients with CAD were identified from the Optum EHR database; most patients were white (n=760 [84%]) and female (n=560 [62%]). Baseline demographics and clinical characteristics of each group can be found in the Table. Of the patients with CAD, 548 (61%) did not receive transfusions and 355 (39%) received ≥1 RBC transfusion. Among patients with CAD who received transfusions, 84% (n=297) had ≥2 RBC transfusions. Out of the 903 patients with CAD, 864 had Hb levels reported and 752 had Hb levels ≤12 g/dL. Forty-four percent (n=329/752) of those CAD patients received ≥1 RBC transfusion. When separated by Hb levels, 18% of patients with Hb 〉10 to ≤12 g/dL (n=19/108); 41% (n=88/216) of patients with Hb ≥8 to ≤10 g/dL; and 52% (n=222/428) of patients with Hb 10 to ≤12 g/dL; 30% (n=128/423) had Hb levels ≥8 to ≤10 g/dL; and 49% (n=206/423) had Hb levels

Description: Background: Prophylactic treatment with factor products has demonstrated superior outcomes and care compared to on-demand treatment in hemophilia patients, including patients with pre-existing joint diseases. However, 40% to 50% of severe or moderate hemophilia A and B patients are still treated on-demand in the US. Recombinant factor VIII and IX Fc fusion proteins (rFVIIIFc and rFIXFc) were the first extended half-life (EHL) products approved in the US (in 2014) with the promise of optimizing prophylactic regimens by achieving low bleeding rates and improving joint health with fewer injections overall. Objective: This is the first real-world study to assess the impact of EHL rFVIIIFc and rFIXFc on overall prophylaxis rates, particularly to understand how patients have transitioned from on-demand treatment. Methods: A retrospective analysis was conducted on aggregate, de-identified United States Specialty Pharmacy Provider (SPP) records from Jan 2014 to June 2018 (data pull on June 14th, 2018). Adult hemophilia patients (age 18 and above) were included for an analysis of treatment regimens prior to and after switching to EHL rFVIIIFc and rFIXFc (on-demand or prophylaxis). The results were descriptively compared to those who switch to the other EHL PEGylated rFVIII and rFIX albumin Fusion Protein (rFIX-FP) and conventional factors. Results: A total of 304 hemophilia A patients who switched to rFVIIIFc and 133 hemophilia B patients who switched to rFIXFc were included in this study. For the hemophilia A and B patients, the median age was 31 and 32 years and median weight was 82 and 79 kg. The proportion of patients who switched from on-demand treatment with conventional factors to prophylaxis treatment with EHL rFVIIIFc and rFIXFc among all patients who switched to these products increased over time since the FDA approval (3 time points: 2014-2015, 2016-2017, and 2018: rFVIIIFc: 13%, 20%, and 21%; rFIXFc: 25%, 29%, and 57%). Such proportions were higher compared to those who switched from on-demand with conventional factors to prophylaxis with the other EHLs (2016-2017, 2018: PEGylated rFVIII: 16%, 18%; rFIX-FP: 18%, 13%, see comparison in the Figure) and with conventional factors (2014-2015, 2016-2017, and 2018: conventional rFVIII: 10%, 7%, and 9%; conventional rFIX: sample size was too small and not suitable for analysis). Discussion: rFVIIIFc and rFIXFc have transformed the paradigm of hemophilia care by shifting on demand patients to prophylaxis significantly faster than conventional factors and any other EHLs to date. This shift is significant as it is helping more hemophilia patients achieve optimal protection through low bleeding rates and improved joint health over the long-term. Figure. Figure. Disclosures Jain: Bioverativ: Employment. Li:Bioverativ: Employment. Krishnan:Bioverativ: Employment. Hagberg:Bioverativ: Employment. Su:Bioverativ: Employment.

Description: Introduction: Immune tolerance induction (ITI) is the standard of care for eradication of inhibitors in subjects with severe hemophilia A. ITI is not always effective and can require a lengthy and burdensome treatment regimen. Those who have previously failed ITI are more likely to fail subsequent ITI. The successful use of recombinant factor VIII Fc fusion protein (rFVIIIFc) for ITI was described in our initial retrospective review of 19 high-risk subjects, including first-time and rescue ITI subjects (Carcao et al, Haemophilia, 2018). These findings indicated that time to tolerization appears to be faster with rFVIIIFc, despite a high-risk profile. It has been postulated that the Fc domain of rFVIIIFc may promote tolerization due to immunomodulatory properties. We report characteristics and ITI outcomes of 6 newly identified subjects, as well as follow-up data from 12 of the 19 subjects included in the original analysis. Methods: A follow-up of subjects enrolled in the original retrospective chart review and clinical outcomes of newly identified males with severe hemophilia A and historical high-titer inhibitors (≥5 BU) treated with rFVIIIFc for ITI is reported from 12 sites in the US and Canada. De-identified data were collected via electronic surveys. This interim analysis was performed on aggregated data collected through July 6, 2018. Data collection is ongoing, with 29 subject charts (19 original subjects and an additional 10) expected by October. Results: Of 25 charts reviewed to date, 9 were first-time ITI and 16 were rescue ITI subjects. Of 9 first-time ITI charts, 7 subjects were from the original study (4 had follow-up data), and 2 subjects were newly identified. Of 16 rescue ITI charts, 12 subjects were from the original study (8 with follow-up data), and 4 subjects were newly identified. All but 1 subject in the first-time ITI group had ≥1 high-risk feature. The median (range) age (n=9) at initiation of rFVIIIFc ITI was 1.4 (0.8-4.3) years and the median (range) time from inhibitor detection to initiation of rFVIIIFc ITI was 1.5 (0-9.4) months (Table 1). The median (range) inhibitor titer at rFVIIIFc ITI initiation was 32 (3-1126) BU/mL, and the dosing regimen of rFVIIIFc ranged from 50 IU/kg 3 times per week (TIW) to 200 IU/kg daily. All 16 rescue ITI subjects had high-risk features. The median (range) age at rFVIIIFc ITI initiation was 7.8 (1.6-48.9) years, with a median (range) time from inhibitor detection to initiation of rFVIIIFc ITI of 7.1 (0.6-43) years (Table 1). The median (range) number of prior ITI courses was 2.5 (1-7). The median (range) inhibitor titer at rFVIIIFc ITI start was 24.2 (0.6-237) BU/mL, and the dosing regimen of rFVIIIFc ranged from 43 IU/kg TIW to 200 IU/kg daily. Eight of 9 first-time ITI subjects achieved a negative Bethesda titer in a median (range) time of 27.2 (3-64.1) weeks and mean (standard deviation [SD]) time of 25.9 (20.7) weeks. All 8 were subsequently tolerized with a median (range) time to tolerization of 29.7 (3-64.1) weeks and a mean (SD) time to tolerization of 33.4 (20.4) weeks (Table 2). One of the 8 subjects, although he achieved a negative Bethesda titer and ultimately was tolerized (time to tolerization: 59 weeks), did so after a complicated course of ITI: he was initially on rFVIIIFc ITI for 15 weeks then was switched to plasma-derived FVIII ITI for 12 weeks. Owing to lack of reduction in inhibitor titer, the subject was switched back to rFVIIIFc ITI. Fourteen weeks later he became Bethesda titer‒negative and achieved tolerance 18 weeks after that. The 9th subject had a reduced titer and continues on rFVIIIFc ITI. Eight of 16 rescue ITI subjects reached negative Bethesda titer in a median (range) time of 29.6 (3-70) weeks (Table 2) and a mean (SD) of 34.9 (25.6) weeks. Of these, 2 subjects were tolerized at 23.1 and 35 weeks, respectively; both have transitioned to rFVIIIFc prophylaxis. Eight subjects continue on rFVIIIFc ITI and 6 transitioned to other ITI treatment regimens. Conclusions: A rapid time to tolerization was achieved in high-risk first-time ITI subjects in a real-world setting. ITI with rFVIIIFc led to rapid negative inhibitor titer in most first-time ITI subjects and many rescue ITI subjects. Faster time to tolerization is expected to improve subject's quality of life, joint health, and healthcare utilization. Findings from this study are being tested in 2 prospective trials using rFVIIIFc for ITI in subjects with hemophilia A with inhibitors (first time and rescue). Disclosures Carcao: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL-Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Shapiro:Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sangamo Biosciences: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioMarin: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Octapharma: Research Funding; Daiichi Sankyo: Research Funding; OPKO: Research Funding; Kedrion Biopharma: Consultancy, Research Funding. Hwang:Bioverativ: Other: PI in clinical research study; Shire: Consultancy; Hema Biologics: Consultancy; Bayer: Consultancy; BPI: Consultancy. Pipe:Catalyst Biosciences: Consultancy; Shire: Consultancy, Research Funding; Spark Therapeutics: Consultancy; Freeline: Consultancy; Bayer: Consultancy; uniQure: Consultancy; Biomarin: Consultancy; Apcintex: Consultancy; Ainylam: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Genentech: Consultancy; Pfizer: Consultancy; CSL Behring: Consultancy; Bioverativ: Consultancy; Nove Nordisk: Consultancy; Siemens: Research Funding; HEMA Biologics: Consultancy; R2 Diagnostics: Research Funding. Ahuja:Shire: Honoraria, Speakers Bureau; Bayer: Honoraria; Bioverativ: Honoraria, Speakers Bureau. Staber:uniQure: Honoraria; Bayer: Honoraria; NovoNordisk: Consultancy. Sun:Octapharma: Research Funding; Novo Nordisk: Consultancy. Ding:Bioverativ: Other: Site PI for clinical research study. Wang:Bayer: Consultancy; Bayer, Novo Nordisk, Octapharma, Genentech, HEMA Biologics, Shire, CSL Behring: Honoraria; Bayer, Bioverative, Novo Nordisk, Octapharma, Shire, Genentech, Biomarain, Pfizer, CSL Behring, HEMA Biologics, Daiichi Sankyo: Research Funding; CSL Behring: Consultancy; Terumo BCT: Other: CPC Clinical Research; Novo Nordisk: Consultancy. Steele:Baxter/SHIRE: Other: Travel, Hotel; Bayer: Honoraria; Roche: Honoraria. Tsao:Bioverativ: Employment. Feng:Bioverativ: Employment. Al-Khateeb:Bioverativ: Other: Consultancy (via Trinity Partners, LLC). Dumont:Bioverativ: Employment. Jain:Bioverativ: Employment.