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

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 <1%) and <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 (>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 <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.

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Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Blood ◽

10.1182/blood-2021-146126 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3184-3184

Author(s):

Robert F. Sidonio ◽

Christine Knoll ◽

Flora Peyvandi ◽

Oleksandra Stasyshyn ◽

Ali Bulent Antmen ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Publicly Traded ◽

Open Label ◽

Inhibitor Development ◽

On Demand ◽

Fviii Inhibitor ◽

Hemostatic Efficacy ◽

Recombinant Fviii

Abstract Background Management of severe hemophilia A includes on-demand treatment or prophylaxis with replacement factor VIII (FVIII) concentrate. FVIII inhibitors can develop following exposure to exogenous FVIII in approximately 30% of previously untreated patients (PUPs), typically in the first 50 exposure days (EDs), with serious complications. This is the first study evaluating the safety, immunogenicity, and hemostatic efficacy of rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA), an extended half-life (EHL) recombinant FVIII, in PUPs with severe hemophilia A. Methods This prospective, open-label, multi-center, phase 3 study (NCT02615691) was conducted in patients ˂6 years of age with severe hemophilia A (FVIII <1%). Patients were previously untreated, or had <3 EDs 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 inhibitory antibodies prior to screening (≥0.6 Bethesda units) were not eligible. 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). Prophylaxis was started before 3 years of age or after a maximum of 2 joint bleeds, whichever occurred first. The primary endpoint was the incidence of FVIII inhibitor development. Secondary endpoints included safety and efficacy (annualized bleeding rate [ABR] and hemostatic efficacy). This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing an inhibitor to FVIII or had developed a confirmed FVIII inhibitor at any time. The data cut-off was 30 August 2019. Demographic and baseline characteristics were summarized using continuous and categorical data. The incidence of FVIII inhibitor development was calculated using the Clopper Pearson exact 95% CI computed for the proportion of patients who developed FVIII inhibitors during the study. ABR was analyzed by point and interval estimates derived from a negative binomial model with treatment regimen as a covariate. The number and percentage of patients reporting adverse events (AEs) and serious AEs (SAEs) was recorded for all patients receiving rurioctocog alfa pegol. 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 (screen failures) did not meet the eligibility criteria and 4 discontinued prior to treatment. 54 patients received prophylaxis and 35 received on-demand treatment at any time during the study period. The mean (SD) patient age at baseline was 11.8 (8.2) months. The number of patients with 0 EDs prior to screening was 36 (61.0%), with 9 (15.3%) patients having 1 ED and 14 (23.7%) having 2 EDs. Overall, 32 patients had a family history of hemophilia A. A large deletion, intron 1 or intron 22 inversion, or substitution nonsense hemophilia gene mutation was present in 29 (49.2%) patients and 21 (35.6%) had either a small deletion, small duplication, or substitution missense gene mutation. Of the 52 patients who qualified for this interim analysis, 10 developed an inhibitory antibody to rurioctocog alfa pegol during the study; the incidence of inhibitor development was 0.192 (95% CI, 0.096-0.325) (10/52). Rurioctocog alfa pegol exposure data and ABRs for patients receiving prophylaxis or on-demand treatment are presented in Table 1. At bleed resolution, hemostatic efficacy was rated by patients as "excellent" for 88/269 bleeds (32.7%) and "good" for 73/269 bleeds (27.1%). Overall, 52 (88.1%) patients receiving rurioctocog alfa pegol experienced a total of 283 AEs, and 13 patients experienced 14 rurioctocog alfa pegol-related AEs (including 10 SAEs). SAEs occurred in 24 patients, 10 of whom experienced 10 treatment-related SAEs of FVIII inhibitor development. 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 a relatively low inhibitor rate compared with other EHL recombinant FVIII products and a safety and efficacy profile consistent with that previously observed for rurioctocog alfa pegol in the treatment of bleeding episodes in patients with hemophilia A. Figure 1 Figure 1. Disclosures Sidonio: Guardian Therapeutics: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biomarin: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Catalyst: Consultancy. Peyvandi: Takeda: Honoraria; Spark: Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Roche: Honoraria; Bioverativ: Honoraria; Grifols: Honoraria. Stasyshyn: Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding; Shire: Consultancy; Grifols: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Antmen: Takeda: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Novo Nordisk: Consultancy. Yeoh: Takeda: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Grifols: Honoraria. Maggiore: IQVIA: Current Employment. Engl: Baxalta Innovations GmbH, a Takeda company: Current Employment; Takeda: Current equity holder in publicly-traded company. Allen: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Tangada: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc: Current Employment.

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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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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 ◽

10.1182/blood.v128.22.3774.3774 ◽

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.

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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 ◽

10.1182/asheducation-2016.1.648 ◽

2016 ◽

Vol 2016 (1) ◽

pp. 648-649 ◽

Cited By ~ 1

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.

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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 ◽

10.1182/asheducation-2011.1.405 ◽

2011 ◽

Vol 2011 (1) ◽

pp. 405-406 ◽

Cited By ~ 5

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.

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Inhibitor Development in Previously Untreated Patients with Severe Hemophilia a Treated with Nuwiq®, a New Generation Recombinant FVIII of Human Origin

Blood ◽

10.1182/blood.v128.22.327.327 ◽

2016 ◽

Vol 128 (22) ◽

pp. 327-327 ◽

Cited By ~ 2

Author(s):

Raina Liesner ◽

Marina Abashidze ◽

Olga Aleinikova ◽

Carmen Altisent ◽

Mark J. Belletrutti ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Hemophilia A ◽

High Titer ◽

Severe Hemophilia ◽

Advisory Committees ◽

Inhibitor Development ◽

Recombinant Fviii ◽

New Generation

Abstract Background Studies have shown that the incidence of inhibitor development varies between FVIII concentrates, with some suggesting that recombinant FVIII (rFVIII) concentrates produced in hamster cell lines pose a greater risk of inhibitor development than plasma-derived (pd) von Willebrand factor (VWF)-containing FVIII (pdFVIII/VWF) products. In the SIPPET study, the cumulative incidence of high-titer inhibitorswith hamster-cell derived rFVIII products was 28.4% vs 18.6% for pdFVIII/VWF (Peyvandi F et al. N Engl J Med 2016; 374:2054-2064). These studies did not include new generation rFVIII products produced in human cell lines. Nuwiq® (Human-cl rFVIII) is the first and only new-generation rFVIII produced in human cells without chemical modification or protein fusion. The pharmacokinetics, efficacy and safety of Nuwiq® have been examined in previously treated patients (PTPs) with severe hemophilia A, and no inhibitors have been reported in 201 PTPs. The immunogenicity, efficacy and safety of Nuwiq® in previously untreated patients (PUPs) with severe hemophilia A is currently being assessed in the ongoing NuProtect study. Methods The NuProtect study was initiated in 2013 and is being conducted in 17 countries and 38 centers worldwide. One hundred evaluable (110 enrolled) male PUPs of all ages and ethnicities are being studied for 100 exposure days (EDs) or a maximum study participation of 5 years. The patients were to have received no treatment with FVIII concentrates or other blood products containing FVIII prior to study entry. The primary objective of the NuProtect study is to assess the immunogenicity of Nuwiq® by determining inhibitor activity (≥0.6 BU) using the Nijmegen modified Bethesda assay in a central laboratory. Intensive screening for inhibitors is scheduled every 3-4 EDs until 20 EDs, then every 10-12 EDs until 100 EDs, and every 3 months until study completion. Secondary endpoints include assessment of hemostatic efficacy in prophylaxis, in the treatment of bleeds and in surgical prophylaxis, as well as safety and tolerability. All patients undergo F8 gene mutation analysis. Results Data from 85 treated PUPs have been included in the first pre-planned interim analysis (May 2016) of which 66 PUPs had ≥20 EDs (by which time the majority of inhibitors are likely to have arisen). The median age at first treatment was 13 months (range: 3-135). Of the 59 patients with available F8 gene mutation analysis, 1 (1.7%) had no identifiable mutation, 44 (74.6%) had mutations conferring a high risk of inhibitor development and 47 (81.0%) had null mutations. Data analysis in May 2016 showed that only 8 of the 66 PUPs treated with Nuwiq® for ≥20 EDs had developed a high-titer inhibitor after a median of 11.5 EDs (range 6-24). Five of the 66 PUPs developed a low-titer inhibitor, 4 (80%) of which were transient. Only 2 patients developed an inhibitor (1 high-titer) after 20 EDs. The cumulative incidence of high-titer inhibitors in PUPs treated with Nuwiq® is 12.8% (95% CI: 4.49-21.15) (Figure 1). The cumulative incidence of low-titer inhibitors was 8.4% (95% CI: 1.28-15.59) and of all inhibitors was 20.8% (95% CI: 10.68-30.95). No patient developed an inhibitor after 25 EDs. The incidence has remained consistent since the start of the study in 2013. Twelve of 13 patients who developed inhibitors had the causative F8 gene mutation detected, all of which were null, and all but one were high-risk. Conclusions PUPs treated with Nuwiq® for ≥20 EDs had 12.8% cumulative incidence of high-titer inhibitorsat the time of interim analysis (8 of 66 PUPs) despite the fact that 81% of patients had gene mutations known to be associated with increased inhibitor risk (e.g. null mutations). These interim data support the low rate of inhibitor development in PUPs treated with Nuwiq® - a human-cell derived (not chemically modified or protein fused) recombinant FVIII. Final data from the NuProtect study are expected in 2018 and will provide further insights into the development of inhibitors in PUPs with severe hemophilia A. Figure 1. Cumulative incidence of inhibitor development Figure 1. Cumulative incidence of inhibitor development Disclosures Liesner: CSL Behring: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Altisent:Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Pfizer: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Octapharma: Consultancy. Belletrutti:Shire Pharmaceuticals (formerly Baxalta): Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; NovoNordisk: Other: Travel support. Borel-Derlon:LFB: Other: Reference expert and national coordinator for VWD; Shire - Baxalta: Research Funding; Octapharma: Research Funding; NovoNordisk: Other: Expert for scientific committee. Ducore:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Octapharama: Membership on an entity's Board of Directors or advisory committees; Baxalta (Shire): Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Sigaud:Shire - Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Risk Differential in Inhibitor Development in the First Days of Treatment By Product Class: A Sippet Analysis

Blood ◽

10.1182/blood.v128.22.330.330 ◽

2016 ◽

Vol 128 (22) ◽

pp. 330-330

Author(s):

Flora Peyvandi ◽

Antonino Cannavò ◽

Isabella Garagiola ◽

Roberta Palla ◽

Frits Rosendaal ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Cox Regression ◽

High Titer ◽

Hazard Ratio ◽

Time Interval ◽

Severe Hemophilia ◽

Inhibitor Development ◽

Fviii Inhibitor ◽

Over Time

Abstract BACKGROUND: Administration of factor VIII (FVIII) concentrates to patients with severe hemophilia A has nearly normalized their life expectancy; however, a substantial number of previously untreated patients (PUPs) develop neutralizing alloantibodies (inhibitors) against FVIII that complicate the benefits of treatment and make the management of these patients difficult and costly. Recently a randomized clinical trial (SIPPET) showed that the risk of inhibitor development is nearly doubled in previously untreated and minimally treated patients with severe hemophilia A treated with recombinant products (rFVIII) compared with plasma-derived (pdFVIII) products containing von Willebrand factor (VWF). AIM: The aim of this post-hoc analysis of the SIPPET study was to assess the early risk of inhibitor development every 5 exposure days (EDs) and to see whether or not there was a difference between the two arms of plasma-derived FVIII and recombinant FVIII products over the course of time of FVIII exposure. METHODS: 251 children were enrolled in the SIPPET study and randomized to receive a single pd or rFVIII (4 different brands of each). The outcomes were any FVIII inhibitor levels ≥ 0.4 Bethesda Units (BU) and high-titer inhibitors (peak levels > 5 BU). Patients were tested for inhibitors before entry and at regular intervals during 50 EDs, 3 years or the development of an inhibitor. Patients who had not reached 50 EDs by the time of study termination were censored. To study the risk over time, survival analysis by Kaplan-Meier and Cox regression were repeated for every 5 EDs to assess the association of source of FVIII with inhibitor development over time. RESULTS: 76 out of 251 patients developed an inhibitor and of those 50 were high-titer; all occurred before 40 EDs. Over the complete observation period, users of rFVIII products had a 87% higher rate of inhibitor development than users of pdFVIII (hazard ratio (HR) 1.87; 95% confidence interval (CI95) 1.17-2.96). The hazard ratio was particularly high during the first 5 EDs, both for all (HR 3.14, CI95% 1.01-9.74) and high-titer inhibitor development (HR 4.19, CI95% 1.18-14.8). After the first 5 EDs, the difference between two arms was less pronounced and quickly dropped to the overall difference of 1.87. Table 1 shows the cumulative incidence per time interval for each of the product classes. CONCLUSION : The risk of inhibitor development during replacement therapy occurs more early (0-5 EDs) in patients treated with rFVIII than in those treated with pdFVIII, and remains high until 15 EDs. For pdFVIII, the highest risk came later (6-10 EDs) and this peak lasted shorter. The results of this analysis shows the relevance of the early exposure days for inhibitor development. Table 1. Table 1. Disclosures Peyvandi: Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; CSL Behring: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Octapharma: Consultancy; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; SOBI: Speakers Bureau; Grifols: Speakers Bureau. Palla:Pfizer: Other: travel support . Mannucci:Bayer: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Speakers Bureau; NovoNordisk: Speakers Bureau.

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

Thrombosis and Haemostasis ◽

10.1055/s-0040-1713097 ◽

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).

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Novel Treatment Approaches in Combination with Rituximab for Immune Tolerance Induction in Severe Hemophilia B.

Blood ◽

10.1182/blood.v110.11.3975.3975 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3975-3975 ◽

Cited By ~ 1

Author(s):

Amanda M. Brandow ◽

Rowena C. Punzalan ◽

Karen Stephany ◽

Craig Helsell ◽

Joan C. Gill

Keyword(s):

Immune Tolerance ◽

High Titer ◽

Tolerance Induction ◽

Factor Ix ◽

Hemophilia B ◽

High Dose ◽

Subdural Hemorrhage ◽

Severe Hemophilia ◽

Immune Tolerance Induction ◽

Novel Approaches

Abstract Although only 4–5% of patients with severe Hemophilia B (HB) develop factor IX (FIX) antibodies that cause inactivation of transfused FIX concentrate (conc), about 1/3 of these are associated with life-threatening anaphylactic reactions; immune tolerance induction (ITI) with high-dose FIX conc is often unsuccessful. We present individualized novel approaches to ITI in 2 boys with severe HB and high-responding inhibitors. ELISA assays utilizing recombinant FIX (rFIX) to capture patient IgG followed by detection with subclass specific monoclonal antibodies were developed to evaluate the characteristics of the factor IX inhibitors before, during and following ITI. Patient 1, a 2 yo boy, presented with a subdural hemorrhage; his inhibitor titer was 14 BU. He was treated with recombinant VIIa (rVIIa), 200 mcg/kg followed by 100 mcg/kg q2 hours plus rFIX conc (BeneFix), 1000 U/kg prior to and post subdural hematoma evacuation; a continuous infusion, 40U/kg/hour rFIX conc was started. FIX:C was >100%, so rVIIa was discontinued and the rFIX infusion was continued to maintain FIX:C levels above 50%. Rituximab (375 mg/m2 q week x 4) was started. On the 6th day, he developed anamnesis; plasma FIX:C dropped to the 20% range in spite of increases in his rFIX conc drip to 68 u/kg/hour. Investigation of right leg edema revealed a large thrombus involving the popliteal, iliac and inferior vena cava with pulmonary embolism. In order to remove the inhibitor antibody and achieve plasma FIX levels that would allow safe anticoagulation with heparin, plasmapheresis with an immunoadsorption Protein A sepharose column (Fresenius) was undertaken. FIX:C levels were unexpectedly lower immediately following each cycle. Investigation of FIX: Ag and anti-FIX IgG, IgG1 and IgG4 by ELISA assays before and after each cycle revealed the presence of FIX: Ag and specific anti-FIX IgG in the column eluates. After the 5th cycle, increasing FIX:C levels allowed weaning of the rFIX conc; the thromboses completely resolved. The patient currently is on standard prophylactic doses of rFIX conc with expected recoveries with no evidence of inhibitor. Patient 2 was a 9 year old boy with a high responding anaphylactoid inhibitor; he had severe and frequent hemarthroses treated with rVIIa with variable success resulting in significant hemophilic arthropathy. He had previously received 2 courses of rituximab with recurrence of inhibitor 3 weeks post-therapy. Therefore, in order to suppress T-cell as well as B-cell immune responses, after desensitization with increasing infusions of rFIX conc, he was treated with cyclophosphamide (10 mg/kg IV on days 2, 3 and PO on days 4 and 5) a standard course of rituximab (375 mg/m2 on days 1, 8, 15, 22), IVIG (100 mg/kg on days 2–5) initially, and high dose rFIX conc, 100U/kg/day. He is now maintained on every-other monthly doses of rituximab and replacement doses of IVIG. As FIX levels rose during ITI, rFIX conc was weaned; eight months after initiation of ITI, he has expected recoveries of FIX: C on standard prophylactic doses of rFIX conc. Investigation of the nature of the patient’s inhibitors revealed that both patients had high titer IgG1 and IgG 4 anti-factor IX antibodies that disappeared after ITI. Unlike the persistence of non-inhibitory IgG4 factor VIII antibodies reported in some patients with hemophilia A, in these two patients, there was no detectable FIX-specific pan-IgG, IgG1 or IgG4 following ITI. We conclude that novel approaches to ITI can be successfully undertaken in severe HB patients with high titer factor IX inhibitors.

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