Long-Term Outcomes of Previously Treated Adult and Adolescent Patients with Severe Hemophilia A Receiving Prophylaxis with Extended Half-Life FVIII Treatments: An Economic Analysis from a United Kingdom Perspective

Abstract Introduction: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care in hemophilia A, given its natural mechanism of action, strict homeostatic regulation, and consistent safety profile. Recombinant FVIII Fc fusion protein (rFVIIIFc) is an extended half-life therapy that demonstrated safety and efficacy in previously treated pediatric, adolescent, and adult subjects with severe hemophilia A in the Phase 3 A-LONG and Kids A-LONG trials (NCT01181128 and NCT01458106, respectively) (Young et al, J Thromb Haemostas, 2015; Mahlangu et al, Blood, 2014). Herein, the final results are reported from ASPIRE (NCT01454739), the long-term extension trial of those 2 studies. Methods: This was an open-label, multicenter, long-term trial of previously treated subjects of all ages with severe hemophilia A. Subjects received 1 of the 4 following regimens: individualized prophylaxis (IP; rFVIIIFc 25‒60 IU/kg every 3-5 days, or twice weekly), weekly prophylaxis (WP; rFVIIIFc 65 IU/kg every 7 days), modified prophylaxis (MP; personalized dosing), or episodic treatment (ET; on-demand dosing based on bleeding episodes). Subjects <12 years of age were eligible for only IP or MP. Investigators could switch a subject's treatment group at any time; therefore, each subject may appear in >1 treatment group. The primary endpoint was development of inhibitors. Secondary endpoints included annualized bleeding rates (ABRs), joint ABRs, spontaneous joint ABRs, exposure days (ED), and factor consumption. Descriptive statistics were used for analysis. Analyses were performed separately based on parent study. Results: A total of 211 subjects (150 were from A-LONG and 61 were from Kids A-LONG) enrolled in ASPIRE, and 186 subjects (132 from A-LONG and 54 from Kids A-LONG) completed the study. Subjects from Kids A-LONG had a median (range) age of 6.0 (2-12) years. Of the subjects from the A-LONG study enrolled to ASPIRE, the median (range) age was 31.0 (13-66) years. Most subjects received IP regardless of parent study (Kids A-LONG: IP [n=59], MP [n=3]; A-LONG: IP [n=110], WP [n=27], MP [n=21], ET [n=13]). No inhibitors were observed throughout the study, and the overall safety profile of rFVIIIFc was consistent with the parent studies and prior interim analyses. ABRs remained low throughout the entirety of ASPIRE in subjects prescribed IP (Table 1). For subjects from the Kids A-LONG study, the median (range) number of ED during ASPIRE was 332.0 (18.0-467.0) days. Total median (range) treatment duration was 166.6 (14.4-203.0) weeks. The median (range) number of ED for A-LONG subjects was 267.5 (8.0-660.0) days. Total median treatment duration was 201.4 (5.1-274.6) weeks. Overall, the median (range) duration of treatment with rFVIIIFc was 4.1 (0.4, 5.9) years. From the end of the parent study to the end of ASPIRE, the rFVIIIFc dosing interval increased for 6.6% and 21.1% of subjects from Kids A-LONG and A-LONG, respectively (Table 2). There was no change in median weekly factor consumption from the end of either parent study to the end of ASPIRE. For subjects from Kids A-LONG, the median (IQR) was 0.0 (0.0‒3.2), while the median (IQR) for those from A-LONG was 0.0 (0.0‒0.0). Conclusions: Throughout up to 4 years of treatment with rFVIIIFc in the ASPIRE extension study, no inhibitors were reported, and low ABRs and extended dosing intervals were sustained. These data are consistent with the well-characterized safety profile and durable efficacy of rFVIIIFc prophylaxis in previously treated subjects of all ages with hemophilia A. Disclosures Nolan: Bayer: Research Funding; CSL Behring: Research Funding; Sobi: Research Funding. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Alnylam: Consultancy, Research Funding, Speakers Bureau; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Amgen: Consultancy; Biomarin: Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Young:Bayer: Consultancy; Bioverativ: Consultancy, Honoraria; Kedrion: Consultancy; Novo Nordisk: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Konkle:Sangamo: Research Funding; Gilead: Consultancy; Spark: Consultancy, Research Funding; BioMarin: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Bioverativ: Research Funding; Pfizer: Research Funding; Shire: Research Funding. Pasi:Shire: Speakers Bureau; Alnylam: Honoraria, Research Funding; Bayer: Speakers Bureau; Octapharma: Honoraria; Pfizer: Speakers Bureau; Biomarin: Honoraria, Research Funding; Sobi: Honoraria; Bioverativ: Honoraria, Research Funding; NovoNordisk: Speakers Bureau; Catalyst Bio: Honoraria; Apcintex: Honoraria. Oldenburg:Novo Nordisk: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Tripkovic:Sobi: Employment. Rudin:Bioverativ: Employment, Equity Ownership.

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Absence of Inhibitor Development in the Routine Clinical Use of Alphanate® in Patients with Severe Hemophilia A: Results From a Long-Term Post-Marketing Surveillance Study.

Blood ◽

10.1182/blood.v114.22.3141.3141 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3141-3141

Author(s):

Charles L. Sexauer ◽

Yasmin Ayob ◽

Madeline Cantini ◽

Miguel Antonio Escobar ◽

Tamiko Fukuda ◽

...

Keyword(s):

Factor Viii ◽

Hemophilia A ◽

Late Onset ◽

Treatment Strategies ◽

Surveillance Study ◽

Severe Hemophilia ◽

Drug Infusion ◽

Post Marketing Surveillance ◽

Previously Treated

Abstract Abstract 3141 Poster Board III-78 Introduction Studies assessing the safety, tolerability and efficacy of a licensed drug are of utmost value for caregivers, patients and authorities to overcome the shortcomings of pre-licensing trials and to obtain information on the behavior of a drug in routine clinical conditions. Moreover, there is a paucity of data addressing the clinical outcome of treatment strategies in patients with severe hemophilia A, an especially vulnerable subset that presents the highest prevalence of antibody inhibitors. Late onset inhibitors may arise in patients who have accumulated hundreds of exposure days or after an intensive treatment episode. Patients and methods To assess the immunogenicity and overall safety associated with long-term use of Alphanate®, a highly purified plasma-derived factor VIII concentrate containing high-molecular weight multimers of von Willebrand Factor, a prospective, non-randomized, multicenter, post-authorization surveillance study was initiated in 2002 with the intention of involving at least 50 evaluable patients. Only previously treated patients (PTPs) diagnosed with severe hemophilia A (<1% FVIII:C) between 6 and 65 years of age who have been previously treated with plasma-derived Factor VIII products other than Alphanate® are eligible to be enrolled. The primary endpoint of the study was the incidence of Factor VIII inhibitors and secondary endpoints were aimed to evaluate product tolerability and hemostatic efficacy. Treatment with Alphanate® was given as needed for routine prophylaxis, bleeding episodes or hemorrhage and prior to physiotherapy or surgical procedures. Results As of December of 2008, the investigation had recruited 31 patients of which 29 (94%) had received at least one infusion of Alphanate® and 21 (68%) had completed the planned 24-30 month observational period with a minimum of 50 exposure days. The mean dose infused was 33.6 IU/kg (range: 18.3-73.1 IU/kg) and volume per patient per infusion was 1774 IU (range 395-3329 IU). Of the 29 subjects that had received approximately a total of 6.9 million units of Alphanate® through 4704 infusions, none had developed inhibitors (0%) and none had seroconverted for hepatitis A, B, C or HIV-1/2. Overall, 12 (42.6%) subjects experienced a total of 50 commonly reported adverse events (AEs), 3 classified as serious, none of which were considered related to the study drug and none occurred during drug infusion. Furthermore, no patients had withdrawn from the study because of AEs and there were no reports of thromboembolic or other thrombotic events. Conclusions The results included herein confirm the excellent immunogenicity and overall safety profile of Alphanate® in the treatment of PTPs with severe hemophilia A. Disclosures Páez: Instituto Grifols S.A.: Employment. Pinciaro:Grifols Biologicals Inc.: Employment. Woodward:Instituto Grifols S.A.: Employment.

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Efficacy and Safety Results from a Phase 3b, Open-Label, Multicenter, Continuation Study of Rurioctocog Alfa Pegol for Prophylaxis in Previously Treated Patients with Severe Hemophilia A

Blood ◽

10.1182/blood-2018-99-110190 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2483-2483 ◽

Cited By ~ 1

Author(s):

Eric S. Mullins ◽

Barbara A Konkle ◽

Catherine E. McGuinn ◽

Werner Engl ◽

Srilatha D. Tangada

Keyword(s):

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Open Label ◽

Advisory Committees ◽

Previously Treated Patients ◽

Previously Treated ◽

Equity Ownership ◽

Recombinant Fviii

Abstract Background: Patients with severe hemophilia A experience substantial morbidity and mortality due to frequent spontaneous and traumatic bleeding episodes, especially in joints. Prophylaxis with standard half-life factor VIII (FVIII) is the standard of care to prevent bleeds. Extended half-life products benefit patients by reducing the number of infusions without impacting the treatment efficacy. Methods: This phase 3b, prospective, open-label, multicenter, continuation study (NCT# 01945593) investigated the safety and efficacy of a PEGylated recombinant FVIII with an extended half-life, rurioctocog alfa pegol (SHP660, BAX 855, ADYNOVATE®, Shire, Lexington, MA, USA), for prophylaxis and treatment of bleeding in patients with severe hemophilia A (FVIII <1%). Eligible children and adults were ≤75 years of age and had either completed a previous rurioctocog alfa pegol study (NCT# 01599819, 01736475, 02210091, 02615691, 01913405, or 02585960) and were willing to immediately transition to the continuation study, or were naïve to rurioctocog alfa pegol but had received treatment with plasma-derived or recombinant FVIII for ≥150 (in patients ≥6 years of age) or ≥50 (in patients <6 years of age) exposure days. Patients received prophylactic rurioctocog alfa pegol at least twice weekly, either at a fixed dose (FD; 45 ± 5 IU/kg in patients ≥12 years of age; 50 ± 10 IU/kg in those <12 years of age; dose adjustment ≤80 ± 5 IU/kg allowed) or with pharmacokinetically (PK)-tailored dosing (≤80 ± 5 IU/kg) to maintain FVIII trough levels ≥3%. The co-primary endpoints assessed were the incidence of FVIII inhibitory antibody development (as measured by ≥0.6 BU in the Nijmegen modification of the Bethesda assay) and the spontaneous annualized bleed rate (ABR). Secondary endpoints included overall hemostatic efficacy ratings and occurrence of adverse events (AEs). Results: The study began in October 2013 and completed in March 2018. Overall, 216 patients receiving prophylaxis were eligible and included in the safety/full analysis dataset (≥1 dose received). Of these, 215 were male, the mean (SD) age at enrollment was 22.8 (15.7) years, the mean (SD) number of documented previous rurioctocog alfa pegol exposure days was 57.0 (39.6), the total ABR over 3-6 months prior to enrollment in the continuation study (including patients naïve to rurioctocog alfa pegol or receiving on-demand or prophylactic treatment with rurioctocog alfa pegol) was mean (SD) 4.7 (12.6), median (range) 0.0 (0-69). Most patients (206; 95.4%) had participated in a previous rurioctocog alfa pegol study. Overall, 215 patients received ≥1 dose in the FD regimen and 25 received ≥1 dose in the PK regimen. These patients received a mean (SD) of 1.72 (0.29) and 2.11 (0.61) prophylactic infusions per week, respectively, with a mean (SD) dose per infusion of 51.15 (8.11) IU/kg and 52.14 (17.03) IU/kg, respectively. None of the patients developed a confirmed FVIII inhibitor in this study and only 1 treatment-related allergic or hypersensitivity reaction (a nonserious mild AE) was reported. Nonserious AEs assessed by the investigators to be related to treatment occurred in 11/216 (5.1%) patients. Serious AEs (SAEs) occurred in 33 (15.3%) patients; there were no SAEs assessed by the investigators to be related to treatment. Descriptive statistics on spontaneous, joint, and total ABR by prophylactic regimen are shown in the Table. The overall total ABR in all patients was mean (SD) 2.5 (3.1), median (range) 1.6 (0.0-19.5). Overall hemostatic efficacy was rated as good or excellent in 88.5% of all bleeds and 89.4% of all bleeds were treated with 1 or 2 infusions. Conclusions: These results show that in previously treated patients with severe hemophilia A, rurioctocog alfa pegol prophylaxis in FD- and PK-tailored regimens was well tolerated and effective. None of the patients developed FVIII inhibitory antibodies, and a decrease in mean total ABR was reported in these patients compared with baseline. Disclosures Mullins: Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konkle:Genentech: Consultancy; CSL Behring: Consultancy; Gilead: Consultancy; Pfizer: Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy; Bioverativ: Research Funding; Shire: Research Funding; Sangamo: Research Funding. McGuinn:CSL Behring: Consultancy; BioMarin: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark: Consultancy, Research Funding; Genentech: Consultancy; Shire: Research Funding; Pfizer: Research Funding. Engl:Shire: Employment, Equity Ownership. Tangada:Shire: Employment, Equity Ownership.

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Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Children with Severe Hemophilia a

Blood ◽

10.1182/blood.v128.22.1414.1414 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1414-1414

Author(s):

Guy Young ◽

Raina Liesner ◽

K John Pasi ◽

Beatrice Nolan ◽

Stefan Lethagen ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Employment Equity ◽

Safety And Efficacy ◽

Dosing Interval ◽

Treatment Groups ◽

Previously Treated ◽

Equity Ownership

Abstract Background: Factor VIII (FVIII) prophylaxis is the standard of care for patients with hemophilia A; however, conventional FVIII products usually require frequent intravenous infusions (3-4 times/week). The safety, efficacy, and prolonged half-life of recombinant FVIII Fc fusion protein (rFVIIIFc) in previously treated children with severe hemophilia A were demonstrated in the phase 3 Kids A-LONG study (NCT01458106, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in children <12 years of age in these studies as of the second interim data cut (8 Dec 2014). Methods: Subjects who completed Kids A-LONG and met the enrollment criteria for ASPIRE could participate in the individualized prophylaxis (IP; 25-80 IU/kg every 2-5 days, or 20-65 IU/kg on Day 1 and 40-65 IU/kg on Day 4 if twice weekly), or the modified prophylaxis (MP; for subjects in whom optimal dosing could not be achieved with IP) treatment groups. Subjects could switch treatment groups in ASPIRE once 12 years of age. For efficacy analyses, data were summarized according to the treatment group in which each subject participated, for the time period they were in that group; thus, subjects may be included in the analysis of more than one treatment group. Outcomes included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL identified and confirmed on 2 separate samples drawn approximately 2 to 4 weeks apart and performed at the central laboratory as measured by the Nijmegen-modified Bethesda assay), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and changes to prophylactic consumption and dosing interval. Outcomes were analyzed over the cumulative duration of Kids A-LONG through the second ASPIRE interim data cut (8 Dec 2014). Results: 61/67 subjects who completed Kids A-LONG enrolled in ASPIRE (<6 y, n = 30; 6 to <12 y, n = 31). As of the second interim data cut, 47 subjects were ongoing in ASPIRE; no subjects changed treatment groups during ASPIRE. Median (IQR) cumulative rFVIIIFc exposure days (EDs) for all subjects who received ≥1 intravenous injection (N = 69) were 190.0 (153.0-208.0) days; the median (interquartile range [IQR]) duration of rFVIIIFc treatment was 1.7 (1.5-2.0) years. No inhibitors were reported. The estimated inhibitor incidence rate (95% confidence interval) was 0.0% (0.0, 5.2) overall and 0.0% (0.0, 6.1) in subjects with ≥100 rFVIIIFc EDs (n = 59). The type and incidence of AEs observed were consistent with those expected for a pediatric hemophilia population. 95.7% of subjects reported ≥1 AE on-study; 36/448 were serious and 2/448 were assessed as related to rFVIIIFc treatment by Investigators. 30.4% of subjects experienced ≥1 serious AE; none were assessed by Investigators as related to rFVIIIFc. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP (n = 57) were generally lower with rFVIIIFc compared with prestudy FVIII (Figure).In the IP group, the ASPIRE Year 1 and Year 2 median (IQR) spontaneous ABRs were 1.0 (0.0-1.0) and 0.0 (0.0-2.3), respectively, for the <6 y cohort (n = 27), and 0.0 (0.0-1.0) and 0.0 (0.0-0.0), respectively for the 6 to <12 y cohort (n = 30).Overall, 79.8% and 95.8% of bleeding episodes were controlled with 1 or ≤2 intravenous injections, respectively. Among subjects treated with FVIII prophylaxis pre-Kids A-LONG who remained on a prophylaxis regimen (n = 54), the median (IQR) dosing interval was lengthened (prestudy FVIII: 2.3 [2.0, 2.3] days; on-study rFVIIIFc: 3.5 [3.5, 3.5] days) and the median (IQR) total weekly prophylactic consumption was similar (prestudy FVIII: 100.0 [78.0, 120.0] IU/kg; on-study rFVIIIFc: 95.0 [75.0, 113.0] IU/kg). Conclusions: Longitudinal data from previously treated children with severe hemophilia A treated with rFVIIIFc in Kids A-LONG/ASPIRE confirm long-term safety, with no inhibitors observed in any subjects, and maintained efficacy in the prevention and treatment of bleeding. Low median ABRs were maintained with extended prophylactic dosing intervals, without increased factor consumption. This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content. Disclosures Young: Biogen: Consultancy, Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Baxter: Consultancy. Liesner:Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; BPL: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Pasi:Biogen: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding. Lethagen:Sobi: Employment. Cristiano:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Winding:Sobi: Employment. Mahlangu:Bayer: Research Funding, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Amgen: Speakers Bureau; Biotest: Speakers Bureau; Baxalta: Consultancy.

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Long-term Efficacy and Safety of rVIII-SingleChain in Patients with Severe Hemophilia A: Interim Results of an Extension Study

10.1055/s-0039-1680221 ◽

2019 ◽

Author(s):

J. Mahlangu ◽

F. Abdul ◽

O. Stasyshyn ◽

B. Korczowski ◽

A. Brainsky ◽

...

Keyword(s):

Hemophilia A ◽

Extension Study ◽

Severe Hemophilia ◽

Efficacy And Safety ◽

Term Efficacy

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Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients

Thrombosis and Haemostasis ◽

10.1055/s-0040-1714214 ◽

2020 ◽

Vol 120 (10) ◽

pp. 1395-1406 ◽

Cited By ~ 1

Author(s):

Iris Garcia-Martínez ◽

Nina Borràs ◽

Marta Martorell ◽

Rafael Parra ◽

Carme Altisent ◽

...

Keyword(s):

Blood Group ◽

Half Life ◽

Robust Regression ◽

Hemophilia A ◽

Illumina Miseq ◽

Activity Levels ◽

Severe Hemophilia ◽

Single Nucleotide Variants ◽

Common Genetic Variants ◽

Recombinant Fviii

AbstractThe pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKFiT device was used to estimate individual PK parameters, and SNVs and clinically reportable F8 variants were simultaneously analyzed in an Illumina MiSeq instrument, using the microfluidics-based Fluidigm Access Array system. The contribution of SNVs to FVIII half-life and clearance was addressed by robust regression modeling, taking into account other modulators. In line with previous studies, we provide robust evidence that age, body weight, and blood group, as well as SNVs in ABO and CLEC4M, participate in the variability of FVIII PK in HA patients. Main results: each copy of the rs7853989 (ABO) allele increases FVIII half-life by 1.4 hours (p = 0.0131) and decreases clearance by 0.5 mL/h/kg (p = 5.57E-03), whereas each additional rs868875 (CLEC4M) allele reduces FVIII half-life by 1.1 hours (p = 2.90E-05) and increases clearance by 0.3 mL/h/kg (p = 1.01E-03). These results contribute to advancing efforts to improve FVIII replacement therapies by adjusting to each patient's PK profile based on pharmacogenomic data. This personalized medicine will decrease the burden of treatment and maximize the benefits obtained.

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Incidence of factor VIII inhibitors throughout life in severe hemophilia A in the United Kingdom

Blood ◽

10.1182/blood-2010-09-308668 ◽

2011 ◽

Vol 117 (23) ◽

pp. 6367-6370 ◽

Cited By ~ 112

Author(s):

Charles R.M. Hay ◽

Ben Palmer ◽

Elizabeth Chalmers ◽

Ri Liesner ◽

Rhona Maclean ◽

...

Keyword(s):

United Kingdom ◽

Factor Viii ◽

Hemophilia A ◽

Interquartile Range ◽

Severe Hemophilia ◽

The United Kingdom ◽

Potential Risk Factors ◽

History Of ◽

Previously Treated Patients ◽

Adjusted Incidence

Abstract The age-adjusted incidence of new factor VIII inhibitors was analyzed in all United Kingdom patients with severe hemophilia A between 1990 and 2009. Three hundred fifteen new inhibitors were reported to the National Hemophilia Database in 2528 patients with severe hemophilia who were followed up for a median (interquartile range) of 12 (4-19) years. One hundred sixty (51%) of these arose in patients ≥ 5 years of age after a median (interquartile range) of 6 (4-11) years' follow-up. The incidence of new inhibitors was 64.29 per 1000 treatment-years in patients < 5 years of age and 5.31 per 1000 treatment-years at age 10-49 years, rising significantly (P = .01) to 10.49 per 1000 treatment-years in patients more than 60 years of age. Factor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being greatest in early childhood and in old age. HIV was associated with significantly fewer new inhibitors. The inhibitor incidence rate ratio in HIV-seropositive patients was 0.32 times that observed in HIV-seronegative patients (P < .001). Further study is required to explore the natural history of later-onset factor VIII inhibitors and to investigate other potential risk factors for inhibitor development in previously treated patients.

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Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Blood ◽

10.1182/blood-2021-155156 ◽

2021 ◽

Vol 138 (Supplement 2) ◽

pp. LBA-5-LBA-5

Author(s):

Lynn Malec ◽

An Van Damme ◽

Anthony Chan ◽

Mariya Spasova ◽

Nisha Jain ◽

...

Keyword(s):

Half Life ◽

Stock Options ◽

Research Funding ◽

Hemophilia A ◽

High Titer ◽

High Dose ◽

Severe Hemophilia ◽

First Time ◽

Inhibitor Titer ◽

Privately Held

Abstract Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer <0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR >66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

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Long-Term Outcomes and Organ Responses with Daratumumab Therapy in Previously Treated Patients with AL Amyloidosis

Blood ◽

10.1182/blood-2019-122152 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1828-1828

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

Erik Eckhert ◽

Stanley Schrier ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cardiac Response ◽

Al Amyloidosis ◽

Long Term Outcomes ◽

Advisory Committees ◽

Renal Response ◽

Cardiac Responses ◽

Previously Treated

Introduction: AL amyloidosis involves deposition of abnormally folded light chains into a wide range of tissues causing end-organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously relapsed/refractory disease. However, data on long-term outcomes to daratumumab, including organ responses, are lacking. Here we present the largest retrospective study to date on patients with previously treated AL amyloidosis treated with daratumumab. Methods: We conducted a retrospective analysis of relapsed/refractory AL amyloidosis patients treated at Stanford University from January 2016 to January 2019. Patients treated with daratumumab, either as monotherapy with dexamethasone (DMT) or in combination with other plasma-cell directed therapies (DCT) were included. Hematologic and organ responses were assessed by consensus guidelines. Hematologic responses were based on the maximal change in the difference between involved and uninvolved free light chains (dFLC). For cardiac response, a >30% and >300 pg/mL decrease in NT-proBNP for patients with initial baseline NT-proBNP ≥650 pg/mL was considered a response. A graded cardiac response metric was also explored with partial response (PR) representing 30-59% reduction, very good partial response (VGPR) ≥60% reduction, and complete response (CR) NT-proBNP <450 pg/mL as previously reported. For renal response, a >30% decrease (by at least 0.5 g/day) in 24-hour urine protein without worsening in creatinine or creatinine clearance by more than 25% in patients with at least 0.5 g/day pretreatment was considered a response. A graded renal response metric was also explored with PR representing 30-59% reduction in proteinuria, VGPR ≥60%, and CR ≤ 200 mg per 24-hour period. Survival data was analyzed using the Kaplan-Meier method. All time-to-event outcomes, including survival and organ responses, were determined from initiation of daratumumab. Results: Eighty-four patients were identified with baseline characteristics at start of daratumumab shown in Table 1. Median duration of follow-up was 16 months. Two-year overall survival (OS) was 83% and median OS was not reached. Median time-to-next-treatment or death was 31 months. Sixty-seven out of 80 evaluable patients (84%) achieved a hematologic response, with 47 patients (59%) achieving a VGPR or better (Figure 1). Sixty-eight patients (81%) had cardiac involvement, and among the 34 evaluable patients, 18 (53%) of evaluable patients achieved a cardiac response with a median response time of 2 months among responders. In terms of a graded cardiac response, 6 patients (18%) were able to achieve cardiac CR, 5 patients (15%) cardiac VGPR, and 7 patients (21%) PR (Figure 2). The median NT-proBNP percent reduction was 64.5% (IQR: 48.3 - 81.1%) and the median absolute reduction was 2395 pg/mL (IQR 1279.5 - 4089.5 pg/mL). Cardiac responses were associated with an improvement in OS (p<0.001, Figure 3), with landmark analysis for cardiac responses at 6-month trending towards statistical significance (100% vs. 51% at 30 months, p=0.052). Fifty-three patients (63%) had renal involvement, and among the 26 evaluable patients, 12 patients (46%) achieved a renal response with a median initial response time of 6 months among responders. Using graded response, 1 patient (4%) achieved renal CR, 7 patients (27%) renal VGPR, 4 patients (15%) renal PR, and 14 patients had no response, worsening creatinine, or were subsequently started on hemodialysis (54%) (Figure 4). The median percent reduction in proteinuria was 74.1% (IQR: 49.2 - 83.1%) and the median absolute reduction in proteinuria was 3.1 g/24 hours (IQR 2.1 - 4.9 g) among responders. There were no significant differences in OS between renal responders and non-responders. Conclusion: Daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve durable hematologic responses as well as improvements in organ function. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Prothena: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. OffLabel Disclosure: Daratumumab in AL amyloidosis

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