ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and Low-Responding Inhibitors: Evidence from a PedNet Study

2020 ◽  
Vol 120 (08) ◽  
pp. 1166-1172
Author(s):  
H. Marijke van den Berg ◽  
Maria Elisa Mancuso ◽  
Christoph Königs ◽  
Roseline D'Oiron ◽  
Helen Platokouki ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Real Life ◽  
Tolerance Induction ◽  
High Dose ◽  
Severe Hemophilia ◽  
Limited Data ◽  
Treatment Regimens ◽  
First Choice ◽  
Lost To Follow Up

Abstract Background Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype. Methods The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry. It included unselected children with severe hemophilia A (factor VIII [FVIII] < 0.01 IU/mL) born between January 1, 1990 and December 31, 2009 who developed clinically relevant inhibitors and were followed-up for at least 3 years after the first positive inhibitor test. Results A total of 260 patients with inhibitors were identified and 68 of them (26%) had low-responding inhibitors (peak < 5 BU/mL). Five patients were lost to follow-up and 63 were included in this study. The median follow-up was 3.7 years (interquartile range: 3.0–7.5). ITI was started in 51/63 (81%) patients. The median time from ITI start to first negative inhibitor titer was similar with low-dose and high-dose ITI regimens (2.5 and 3.1 months, respectively). Ten of the 12 patients who did not receive ITI were treated with regular prophylaxis and reached a negative titer after a median of 6.5 months. Bleeding rate was low in all patients with no difference between treatment regimens. Conclusion In children with low-responding inhibitors negative titers were reached with regular FVIII treatment irrespective of the regimen (i.e., prophylaxis or ITI).

scholarly journals Rurioctocog Alfa Pegol Use in Immune Tolerance Induction: Interim Results from an Open-Label Multicenter Clinical Trial in Previously Untreated Patients with Severe Hemophilia a

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3185-3185
Author(s):  
Robert F. Sidonio ◽  
Alexis A. Thompson ◽  
Flora Peyvandi ◽  
Canan Albayrak ◽  
Seoh Leng Yeoh ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
High Dose ◽  
Severe Hemophilia ◽  
Publicly Traded ◽  
Open Label ◽  
Fviii Inhibitor ◽  
Recombinant Fviii

Abstract Background The development of inhibitors to exogenous factor VIII (FVIII) is a serious treatment complication in patients with hemophilia A. Immune tolerance induction (ITI) is the only proven method for the eradication of FVIII inhibitors. This prospective, multicenter, open-label, phase 3 study (NCT02615691) is being conducted to determine the safety, immunogenicity, and efficacy of the extended half-life (EHL) recombinant FVIII rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in previously untreated patients (PUPs) with severe hemophilia A. The data presented here aims to evaluate the efficacy and safety of ITI therapy with rurioctocog alfa pegol in patients who developed FVIII inhibitors. Methods Eligible patients were ˂6 years of age with severe hemophilia A (FVIII &lt;1%) and &lt;3 exposure days (ED) to rurioctocog alfa pegol, octocog alfa, or plasma transfusion at any time prior to screening. Patients with detectable FVIII inhibitory antibodies at screening or a history of FVIII inhibitors prior to screening (≥0.6 Bethesda units [BU]) were excluded from the study. Patients received intravenous rurioctocog alfa pegol as prophylaxis (25-50 IU/kg, up to 80 IU/kg ≥1 × weekly) and/or on-demand therapy (10-50 IU/kg, up to 80 IU/kg depending on bleed severity). Patients who developed a high-titer FVIII inhibitor (&gt;5.0 BU) or low-titer FVIII inhibitor (≥0.6 BU to ≤ 5.0 BU) plus poorly controlled bleeding despite increased FVIII doses and/or bypassing agents, were eligible for ITI therapy. Dosing for ITI therapy ranged between 50 IU/kg 3 × weekly (low dose) and 100-200 IU/kg daily (high dose) at investigator discretion. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing confirmed inhibitors to rurioctocog alfa pegol or had developed a confirmed FVIII inhibitor at any time. The data cut-off was 30 August 2019. The primary endpoint of this study was the success rate of ITI with rurioctocog alfa pegol. Success was defined as an inhibitor titer persistently &lt;0.6 BU, FVIII incremental recovery (IR) ≥66% of baseline following 84- to 96-hour wash-out, and FVIII half-life ≥6 hours (dependent on protocol version). Secondary endpoints included the rates of partial success and failure of ITI, and annualized bleeding rate (ABR) during ITI. The number and percentage of patients reporting adverse events (AEs) and serious AEs (SAEs) were recorded for patients treated with ITI. Informed consent and ethics approval were obtained. Results As of the data cut-off, 59 (73.8%) of 80 enrolled patients had received ≥1 dose of rurioctocog alfa pegol; 18 patients did not meet the eligibility criteria (screen failures) and 4 discontinued prior to treatment. 10 patients developed an inhibitor to rurioctocog alfa pegol (high titer: n=5; low titer: n=5), of these, 6 patients were enrolled to receive ITI and only 5 of these (83.3%) actually received ≥1 dose of rurioctocog alfa pegol for the treatment of FVIII inhibitors (low dose: n=3; high dose: n=2). Of these 5 patients, 1 completed high-dose ITI therapy and this was successful (based on negative inhibitor titer and IR ≥66% of baseline). The remaining 4 patients were continuing in the study at the time of the data cut-off. Of the 5 patients who received ≥1 dose of ITI, 4 (80.0%) had a total of 17 AEs, 3 (60.0%) experienced 8 SAEs, and 1 experienced a treatment-related SAE of FVIII inhibition. It is important to note that the onset date of FVIII inhibitor development in this patient occurred prior to initiation of ITI. One patient experienced 2 catheter-related AEs, both of which resolved, and no patients experienced thrombotic AEs, study procedure-related AEs, or AEs leading to discontinuation of treatment. Discussion This is the first prospective study of the EHL recombinant FVIII rurioctocog alfa pegol for the treatment of PUPs with severe hemophilia A. These preliminary results demonstrate that rurioctocog alfa pegol has a safety profile consistent with previous studies. In addition, these interim data suggest that using a high-dose regimen for ITI therapy is potentially efficacious in PUPs who have developed FVIII inhibitors, although only 1 patient had completed ITI at the time of this interim analysis. Disclosures Sidonio: Pfizer: Consultancy; Octapharma: Consultancy, Research Funding; Catalyst: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Guardian Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Biomarin: Consultancy. Thompson: Global Blood Therapeutics: Current equity holder in publicly-traded company; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Peyvandi: Bioverativ: Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Spark: Honoraria; Takeda: Honoraria; Roche: Honoraria; Grifols: Honoraria. Yeoh: Grifols: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Takeda: Honoraria. Lam: Takeda: Consultancy, Honoraria; Roche: Honoraria; Bayer: Honoraria; Pfizer: Consultancy, Honoraria. Maggiore: IQVIA: Current Employment. Engl: Takeda: Current equity holder in publicly-traded company; Baxalta Innovations GmbH, a Takeda company: Current Employment. Allen: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.: Current Employment. Tangada: Takeda Development Center Americas, Inc: Current Employment; Takeda: Current equity holder in publicly-traded company.

Risk Factors for the Development of High-Titer Inhibitors in 260 Children with Severe Hemophilia a Born Between 1990 and 2009: The Remain Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3774-3774
Author(s):  
Maria Elisa Mancuso ◽  
Kathelijn Fischer ◽  
Elena Santagostino ◽  
Johannes Oldenburg ◽  
Helen Platokouki ◽  
...  
Keyword(s):  
Family History ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
History Of

Abstract The development of anti-FVIII antibodies (i.e., inhibitors) is the major side effect of severe hemophilia A treatment. Inhibitors mainly develop in children during the first 50 exposure days and are classified in low-and high-titer (i.e., peak titer < or > 5 UB/ml). High-titer inhibitors have the major clinical impact. At diagnosis however, the real nature of the antibody is not clear in all patients, since some low-titer inhibitors may progress to high-titer. The determinants of the evolution from low- to high-titer inhibitors are still unclear and the aim of the present study was to investigate potential risk factors associated with the progression from low- to high-titer inhibitors. This study is a follow-up study of the PedNet Registry and includes 260 children with severe hemophilia A and clinically relevant inhibitors, born between 1990 and 2009 and consecutively recruited from 31 hemophilia centers in 16 countries. Clinical and laboratory data were collected from the date of first positive inhibitor test and covered a minimum of 3-years follow-up. Factors potentially associated with progression from low- to high-titer inhibitor development were analyzed using univariate and multivariate logistic regression. F8 mutation type was known in 247 patients (95%), including 202 (82%) null mutations (i.e., large deletions, nonsense mutations and inversions). Positive family history of inhibitors was present in 37 of 99 (37%) with positive family history of hemophilia. At diagnosis 49% (n=127) had low-titer inhibitors, however, upon FVIII re-exposure, 50% of low-titer inhibitors progressed to high-titer and only 25% of patients (n=69) had persistent low-titer inhibitors. Within the first 3 years of follow-up, immune tolerance induction (ITI) was equally implemented in around 80% of low-and high-titer patients but it was started later in children with high-titers (median time to ITI start 4.5 vs 0.3 months; p<0.001) in whom daily regimens and high-dose FVIII were more frequently adopted (89, 67% vs 41, 50% and 98, 74% vs 35, 43%; p=0.01 and <0.001, respectively). Overall high-titer inhibitor development was associated with null F8 mutations (OR 2.8, 95%CI 1.4-5.5) and family history of inhibitors (OR 3.9, 95%CI 1.2-12.6). The progression from low- to high-titer inhibitors during follow up, was associated with the use of high-dose ITI regimens (i.e., >100 IU/kg/day) with an OR of 3.9 (95%CI 1.5-10.0), independent from the effects of F8 mutation type (adjusted OR 3.6, 95%CI 1.4-9.8) and family history of inhibitors (adjusted OR 6.7, 95%CI 1.1-42.6). No difference was found by comparing the use of daily versus non-daily ITI. In conclusion, in a cohort of 260 children with severe hemophilia A and inhibitors, 49% presented with low-titers at diagnosis and 46% of them progressed to high-titers during follow-up. Progression to high-titer inhibitors was associated with the use of high-dose ITI. These results suggest that intensive ITI should be avoided as initial strategy in low-titer inhibitor patients. Disclosures Mancuso: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Fischer:Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Santagostino:Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Sobi: Consultancy; Biogen Idec: Consultancy; Roche: Consultancy; Grifols: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Liesner:BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding.

scholarly journals What is the role of an extended half-life product in immune tolerance induction in a patient with severe hemophilia A and high-titer inhibitors?

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 648-649 ◽  
Author(s):  
Maissaa Janbain ◽  
Steven Pipe
Keyword(s):  
Immune Tolerance ◽  
Half Life ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
High Dose ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
History Of

Abstract A 10-year-old boy presents with a history of severe hemophilia A and high-titer inhibitor that had failed high-dose immune tolerance induction (ITI) with a recombinant factor VIII (rFVIII) product and a plasma-derived FVIII product. You are asked by his mother whether he should be tried on ITI with an extended half-life product, in particular, consideration of a rFVIIIFc concentrate.

Detection of Inhibitor Development in Hemophilia A Patients From the Time of First Exposure to Factor VIII: Performance of An ELISA-Based Factor VIII Antibody Screening Assay.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3482-3482
Author(s):  
Joan Cox Gill ◽  
Michelle A Stapleton ◽  
Nancy Kern ◽  
Karen Stephany ◽  
Megan Gavin
Keyword(s):  
Factor Viii ◽  
Immune Tolerance ◽  
Neutralizing Antibodies ◽  
Hemophilia A ◽  
Venous Access ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Antibody Screen

Abstract Abstract 3482 Poster Board III-419 About 25% of patients with severe hemophilia A develop neutralizing antibodies to factor VIII (FVIII), termed inhibitors, within a median of eleven exposure days to factor VIII containing therapeutic replacement products. Effective monitoring of inhibitor development in young hemophilic children is hampered by their frequently difficult venous access and their limitations on blood sample size, often making it a challenge to obtain samples suitable to carry out standard PTT based Bethesda assays. We evaluated the performance of the Factor VIII Antibody Screen (GTI Diagnostics, Waukesha, WI), an ELISA-based assay to detect FVIII antibodies in a cohort of hemophilia A patients as they were first exposed to FVIII replacement therapy for treatment of hemorrhages. FVIII antibodies were detected in the assay by incubation of duplicate patient samples and controls in microtiter wells coated with recombinant FVIII. After washing, bound FVIII antibody was detected with alkaline phosphatase conjugated goat anti-human IgG, and a colorimetric endpoint (optical density [OD] read at 405or 410 nm by spectrophotometry) determined in an ELISA plate-reader after incubation with p-nitrophenyl phosphate. Samples were considered positive if the average of the sample ODs was higher than the positive controls or negative if the average of the sample ODs was lower than the negative controls. Thirty consecutively identified patients with severe hemophilia A, who were enrolled in a longitudinal inhibitor study, and had samples of serum or plasma banked from the time of their first exposures to FVIII-containing therapeutic products were included. Patients were followed a median of 15.5 years (range 2 – 23 years). Nineteen (63%) of the patients never developed clinical or laboratory evidence of inhibitor development during follow-up. Eleven of the thirty (37%) developed an inhibitor during follow-up; one of these occurred in a 5 year-old after more than 650 exposure days to factor VIII concentrate. There were no differences in the time-to-first-exposure or pattern of hemorrhages in the two groups with the exception that all post-circumcision hemorrhages (N=6) occurred in the non-inhibitor group. In the non-inhibitor group, banked samples were selected corresponding to 0, 5, 10 and >50 factor VIII exposure-days; none of these samples had a positive result in the FVIII antibody screen ELISA. In the 11 inhibitor patients, banked samples were selected that corresponded with the earliest available sample, a sample obtained prior to the first positive Bethesda assay, the first Bethesda positive sample, a sample obtained at the initiation of immune tolerance induction (ITI), the peak Bethesda titer sample, the first negative Bethesda titer sample during ITI, and the most recent sample. All eleven of those who developed an inhibitor underwent successful immune-tolerance therapy with high dose (100 units/kg/day) factor VIII infusions. All Bethesda positive samples were positive by the FVIII antibody screen ELISA with one exception, a sample from one of the inhibitor patients just prior to development of a recurrent inhibitor. There were 5 Bethesda assay negative/FVIII antibody screen ELISA positive samples in the inhibitor patients; each of these samples had been obtained during ITI at 24-48 hours post factor VIII concentrate infusions, and were concordant with lower than expected factor VIII recoveries. We conclude that the ELISA-based FVIII antibody screen is sensitive and specific for the detection of factor VIII antibodies in patients with hemophilia A who develop inhibitors. Because it can be carried out with small serum as well as plasma samples, it provides a convenient method to obtain results in small patients with poor venous access, although quantification of the antibody titer in positive samples would require additional sample to carry out a PTT-based Bethesda assay. Unlike the Bethesda assay, this ELISA-based assay was able to detect antibodies in transfused patients undergoing ITI without the need for a prolonged washout period. Prospective studies to determine the utility and cost-effectiveness of this method are warranted. Disclosures: Gill: GTI Diagnositcs: Consultancy. Stapleton:GTI Diagnostics: Employment. Kern:GTI Diagnostics: Employment.

scholarly journals What is the Evidence for the Use of Immunomodulatory Agents to Eradicate Inhibitory Antibodies in Patients with Severe Hemophilia A Who Have Previously Failed to Respond to Immune Tolerance Induction?

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 405-406 ◽  
Author(s):  
Michael U. Callaghan ◽  
Patrick F. Fogarty
Keyword(s):  
Immune Tolerance ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
High Dose ◽  
Severe Hemophilia ◽  
Inhibitory Antibody ◽  
Immunomodulatory Agents ◽  
Immune Tolerance Induction ◽  
Inhibitory Antibodies

Abstract An 18-year-old man has severe hemophilia A that has been complicated by a high-titer inhibitory antibody (peak 170 BU/mL). He had previously failed a trial of immune tolerance induction (ITI) using daily high-dose (100 units/kg/d) factor VIII (FVIII) for 20 months and would like to know if immunomodulatory agents, with or without another course of ITI, might eradicate the inhibitor.

scholarly journals Updated Follow-up of the Alta Study, a Phase 1/2, Open Label, Adaptive, Dose-Ranging Study to Assess the Safety and Tolerability of SB-525 Gene Therapy in Adult Patients with Severe Hemophilia A

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2060-2060 ◽  
Author(s):  
Barbara A. Konkle ◽  
Kimo Stine ◽  
Nathan Visweshwar ◽  
Thomas J. Harrington ◽  
Andrew D. Leavitt ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hemophilia A ◽  
High Dose ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Employment Equity ◽  
Dose Cohort ◽  
Fviii Activity ◽  
Equity Ownership

Introduction: Hemophilia A is a rare blood disorder caused by an F8 variant resulting in insufficient Factor VIII (FVIII) activity. Updated results and follow-up of an ongoing gene therapy study in patients with severe hemophilia A are presented. Methods: The Alta study is a dose-ranging, single-dose study of SB-525 gene therapy, a recombinant adeno-associated virus (rAAV6) vector encoding an F8 gene. SB-525 was injected into 11 patients in 4 cohorts of 2 patients each across 4 ascending doses (9e11, 2e12, 1e13 and 3e13 vg/kg) with expansion of the high dose cohort by 3 additional patients. Endpoints included: safety events, changes in circulating FVIII activity, FVIII antigen, FVIII usage, and frequency and severity of bleeding. Results: In the third cohort (1e13 vg/kg), a single infusion of SB-525 resulted in stable and clinically relevant increases in FVIII activity. Patients in the fourth cohort (high dose, 3e13 vg/kg) achieved FVIII levels within the normal range (Table 1), with no bleeding events reported up to 24 weeks post-injection. Patients treated at 3e13 vg/kg did not require FVIII replacement therapy following the initial prophylactic period of up to approximately 3 weeks post-SB-525 administration. No bleeding events were observed in any of the patients treated at the 3e13 vg/kg dose. One patient had a treatment-related serious adverse event of hypotension and fever, with symptoms of headache and tachycardia, which occurred ~6 hours after completion of the vector infusion and resolved with treatment within 24 hours. In the three first cohorts, no ALT elevation requiring more than 7 days of corticosteroid treatment was observed. Of the 5 patients treated to date in the high dose cohort, 3 followed for at least 8 weeks showed transient and mild (grade 1) ALT elevations. All responded to corticosteroids within one week. At the time of abstract submission, all patients were off corticosteroids. FVIII antigen was assessed by ELISA, and preliminary results from the high dose cohort showed a good correlation by chromogenic assay between the specific activity of SB-525 derived FVIII and Xyntha, a recombinant B-domain deleted protein control. Dosing in the fourth cohort is ongoing, and additional analyses of the trial data including FVIII levels, bleeding rate and factor usage will be presented as available. Four- to 11-month follow-up data on all patients in the fourth dose cohort will also be presented. Conclusions: To date, treatment with a single infusion of SB-525 gene therapy resulted in dose-dependent and sustained increases in FVIII levels, with a substantial decrease in FVIII usage, and no bleeding episodes recorded in the highest dose cohort. Patients treated in the highest dose cohort achieved FVIII activity in the normal range. No ALT elevations persisting longer than 7 days were observed in the first three dose cohorts. The study is ongoing, and the results support further development of SB-525 for the treatment of severe Hemophilia A. Disclosures Giermasz: uniQure: Consultancy, Other: Research; Sangamo: Other: Research; Bioverativ/Sanofi: Consultancy, Speakers Bureau; BioMarin: Consultancy, Other: Research; Genentech/Roche: Consultancy, Other: Research, Speakers Bureau. Arkin:Pfizer: Employment, Equity Ownership. Di Russo:Pfizer: Employment, Equity Ownership. Snyder:Sangamo Therapeutics: Employment. Woolfson:Sangamo Therapeutics: Employment, Equity Ownership. Rouy:Sangamo Therapeutics: Employment, Equity Ownership.

Durability of ITI Utilizing Rfviiifc

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3793-3793
Author(s):  
Margaret V. Ragni ◽  
Lynn M. Malec ◽  
Janna M. Journeycake
Keyword(s):  
Immune Tolerance ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Tolerance Induction ◽  
Severe Hemophilia ◽  
Immune Tolerance Induction ◽  
Viii Inhibitor ◽  
Inhibitor Titer

Introduction: The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy in patients with severe hemophilia A who develop inhibitors. The long-acting recombinant factor VIII Fc fusion protein, rFVIIIFc (Eloctate™), which is safe and effective in the prevention and treatment of bleeding events, may promote tolerance to FVIII as shown in preclinical animal models and an inhibitor prone child, as Fc suppresses immunoregulatory Tcells to proteins to which Fc is attached. We therefore previously hypothesized rFVIIIFc would provide effective ITI, specifically shortening and simplifying ITI, and have previously described successful inhibitor eradication in three patients. Long-term follow-up data after successful ITI in patients with severe hemophilia remains limited. In the International Immune Tolerance Induction study, at 1-year follow-up, 6 of 66 subjects who had achieved tolerance demonstrated evidence of relapse at a median of 9.5 months. Of these 6 subjects, 1 had a measurable inhibitor titer and 5 had reduced FVIII recovery. We aim to provide follow-up data on our cohort of patients who had successful inhibitor eradication utilizing rFVIIIFc for ITI. Methods: Immune tolerance induction was initiated in three patients with severe hemophilia A and anti-VIII >5 B.U., in two as initial ITI (Pt. 1, 3), and one as salvage (Pt. 2) after failing to achieve ITI with standard rFVIII due to poor compliance. Follow-up was scheduled every 6-8 weeks, with planned determination of FVIII half-life once the anti-FVIII fell to <0.6 B.U. Tolerance was a priori defined as achieving anti-FVIII <0.6 B.U., FVIII recovery of at least 60%, and half-life (t½) >6 hours. Once a t½ >6 hours was documented, incremental reduction to rFVIIIFc occurred. Patients continued to be followed by their local HTC as per standard of care. Results: ITI was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc every other day or three times weekly per MD discretion. The time to initial anti-FVIII <0.6 B.U. was 4-12 weeks. Patient 1 and 2 were able to achieve tolerance, with a FVIII recovery of at least 60%, and half-life (t½) >6 hours, at weeks 18 and 17, respectively, after initiation of ITI. Patient 3 has improved but is not yet fully tolerized, as evidenced by 57% recovery and a t½ of approximately 7 hours. Anti-VIII inhibitor titers remain negative at 15, 16 and 15 months, from the initiation of ITI in patients 1, 2, and 3 respectively. Patients 1 and 2 have been able to decrease their post ITI prophylaxis dosing regimen to 80 IU/kg and 65 IU/kg three times a week while maintaining a FVIII trough of >1%. No patients were maintained on bypassing prophylaxis during ITI and no patients have experienced hemarthroses or other major bleeding event since the initiation of ITI. Discussion: Immune tolerance induction was successful in three children with inhibitors using rFVIIIFc, including a child previously failing rFVIII ITI. The time to anti-FVIII=0 was 4-12 weeks, significantly shorter than with current rFVIII ITI. At a mean duration of follow up of 15.3 months, all patients achieved an anti-VIII inhibitor titer of 0 B.U. Repeat pharmacokinetics studies will be available at planned subsequent follow-up visit. To date, these data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in three children with inhibitors, and has provided durable and continuing immune tolerance to FVIII. Whether rFVIIIFc ITI will be successful and durable in a larger cohort of children with severe hemophilia A will require prospective studies. A prospective observational study of rFVIIIFc ITI pre- and post-ITI T cell responses in children with hemophilia and inhibitors, the Hemophilia Inhibitor Response to Eloctate (HIRE) Study, has begun recruitment. Disclosures Ragni: SPARK: Research Funding; Shire: Consultancy; Novo Nordisk: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding. Malec:Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding; Biogen: Consultancy. Journeycake:CSL: Consultancy; Biogen: Consultancy; Baxalta/Shire: Consultancy.

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

Blood ◽  
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 &lt;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 &gt;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

scholarly journals Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 378-383 ◽  
Author(s):  
IM Nilsson ◽  
E Berntorp ◽  
O Zettervall ◽  
B Dahlback
Keyword(s):  
Factor Viii ◽  
Hemophilia A ◽  
Protein A ◽  
Gel Filtration ◽  
Tolerance Induction ◽  
Factor Ix ◽  
High Dose ◽  
Void Fractions ◽  
Igg4 Antibody ◽  
Induction Of Tolerance

Abstract We recently described tolerance induction with factor VIII/IX, cyclophosphamide, and high-dose intravenous IgG in hemophilia A or B patients with coagulation inhibitory antibodies. Circulating noninhibitory antibodies complexed with factor IX have been demonstrated in tolerant hemophilia B patients. Similar findings are now described in six tolerant hemophilia A patients. Complexes between factor VIII and the ‘tolerant’ antibody were demonstrated by subjecting plasma to gel filtration chromatography, void fractions containing factor VIII/vWF complexes being collected and adsorbed to protein A. Using 125I-labeled F(ab')2 fragments against IgG subclass and factor VIII antigen, complexes between an IgG4 antibody and factor VIII were found to adsorb to protein A. After infusion of factor VIII to tolerant patients, all factor VIII circulated in complex with IgG4 antibody. In three of the patients, the ‘tolerant’ antibodies inhibited an ELISA specific for factor VIII light chain but, unlike the pretolerant antibodies, did not bind radiolabeled factor VIII heavy chain. Although after induction of tolerance the patients still have circulating IgG4 antibodies against factor VIII, the antibodies differ in specificity, lack coagulation inhibitory activity, and do not enhance the rate of elimination of factor VIII.

Sign in / Sign up

Export Citation Format

Share Document