Interim Analysis of the Extension Study with rVIII-SingleChain in Previously Untreated Patients (PUPs) with Severe Hemophilia A (CSL627-3001)

Background: rVIII-SingleChain is a novel B-domain truncated recombinant Factor VIII comprised of covalently bonded FVIII heavy and light chains designed to have a high binding affinity to von Willebrand factor. Aims: This multicenter, open-label, phase III extension study investigates the safety and efficacy of rVIII-SingleChain for prophylaxis and on-demand treatment of bleeding episodes in 50 previously untreated patients (PUPs) for at least 50 Exposure Days (EDs). An ITI substudy was implemented to allow the use of rVIII-SingleChain to attempt inhibitor eradication for PUPs who develop an inhibitor to FVIII. Method: PUPs with severe hemophilia A (no prior exposure to any FVIII product, and endogenous Factor VIII <1%) were assigned by the investigator to a prophylaxis or on-demand treatment regimen. Inhibitors were assessed monthly. Patients diagnosed with an inhibitor to FVIII (two consecutive central laboratory [CL] results of ≥0.6 BU/mL) could be enrolled into the ITI substudy or remain in the main study. The ITI substudy regimens are: 50 IU/kg 3x/week (low), 100 IU/kg daily (medium), or 200 IU/kg daily (high). Inhibitor eradication was defined as two consecutive CL results of <0.6 BU/mL. One subject was withdrawn per protocol due to high titer inhibitor diagnosis prior to ITI substudy implementation. Results: As of March 28, 2019, 23 PUPs were treated with rVIII-SingleChain. Median age: 1 y (range 0-5). Mean (SD) time on study: 21.6 (12.6) months. Race distribution; Asian 2, Black 7, White 14. There have been 147 bleeding events treated with rVIII-SingleChain rated for hemostatic efficacy by the investigator. While patients were inhibitor negative, the overall treatment success (rating of excellent/good) was 93%, and the annualized spontaneous bleeding rate (AsBR) was 0.58. The adverse event profile was as expected, as the most frequently occurring adverse events were upper respiratory tract infections and inhibitors. Twelve subjects (52%) [95% CI 31%, 73%] were diagnosed with an inhibitor to FVIII; 6 (26%) high titer (peak titer ≥5 BU/mL), and 6 (26%) low titer (peak titer <5 BU/mL). Seven of 11 inhibitor negative subjects achieved >50 EDs, 1 achieved 47 EDs, and 3 achieved <20 EDs. The median ED for inhibitor development (initial result) was 10, range 4-23. All PUPs enrolled had ≥1 risk factor for inhibitor development (Table 1) including genetic mutation, age of first exposure, initial treatment reason and assigned regimen, as well as bleeding events and infections; inhibitor positive and negative subjects were comparable. Of the 12 inhibitor positive subjects, 11 continued treatment with rVIII-SingleChain, 7 were treated with approximately 50 IU/kg 3x/week (low dose ITI), 3 with an increased prophylaxis regimen, 1 with no change in regimen, and 0 with high or medium dose ITI regimen (Table 2). Eight of 11 (73%) inhibitor positive subjects (2 high titer, 6 low titer) achieved eradication; 5 low titer subjects were eradicated within 6 months. The clinically relevant inhibitor subjects (2 high titer, and 1 persistent low titer) achieved eradication in a median of 15.7 months, 2 using low dose ITI, and 1 using increased prophylaxis. Eradicated patients were negative for a median of 13.6 months, and no inhibitor relapse was observed. Three remaining inhibitor positive patients are early in their rVIII-SingleChain inhibitor treatment (2.1, 3.5, and 5.4 months). Detailed analysis of the antibody signature was performed, and revealed epitope isotypes and subclass distribution comparable to other FVIII molecules. Conclusion: Overall, rVIII-SingleChain demonstrates a positive benefit:risk profile for safety and efficacy in PUPs. The crude high titer inhibitor rate is 26% which is consistent with other rFVIII products, whereas the crude low titer inhibitor rate is currently 26% which is on the higher end in comparison to other rFVIII products. Immunological analyses suggest a low affinity antibody population in subjects with low titer inhibitors. The majority of subjects (73%) who continued treatment with rVIII-SingleChain achieved eradication on a low dose ITI or prophylaxis regimen of approximately 50 IU/kg 3x/week or less. Additional time on study for the currently enrolled subjects is required to determine the final inhibitor and eradication rates in PUPs treated with rVIII-SingleChain. Disclosures Santagostino: Pfizer: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Shire / Takeda: Consultancy, Speakers Bureau. Koenigs:Roche: Consultancy; CSL Behring: Research Funding, Speakers Bureau; Bayer Vital GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; Intersero: Research Funding; Grifols: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Djambas Khayat:Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Lucas:CSL Behring: Employment. Salazar:CSL Behring: Employment. Brainsky:CSL Behring: Employment. Chung:CSL Behring: Employment. Goldstein:CSL Behring: Employment. Mahlangu:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomarin: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Unique: Research Funding; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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The EPIC Study: A Clinical Trial To Assess Whether Early Low Dose Prophylaxis In The Absence Of Immunological Danger Signals Reduces Inhibitor Incidence In Previously Untreated Patients (PUPs) With Hemophilia A

Blood ◽

10.1182/blood.v122.21.576.576 ◽

2013 ◽

Vol 122 (21) ◽

pp. 576-576 ◽

Cited By ~ 4

Author(s):

Guenter Auerswald ◽

Karin Kurnik ◽

Jan Blatny ◽

Armin J Reininger

Keyword(s):

Research Funding ◽

Low Dose ◽

Hemophilia A ◽

Venous Access ◽

Patient Specific ◽

Missense Mutations ◽

Severe Hemophilia ◽

Prophylactic Regimen ◽

Inhibitor Development ◽

Danger Signals

Abstract Background Inhibitor development is a complex, multifactorial immune response involving both patient-specific and treatment-related factors. Of the known risk factors, intensive treatment at an early age has been shown to be significant, and clinical observations have suggested that early prophylaxis (i.e. first exposure to FVIII in the absence of a bleed in the first year of age) may protect patients from inhibitor development by inducing FVIII tolerance. Aim This study aimed to assess prospectively if a once-weekly, low-dose prophylactic regimen started before 1 year of age and before the onset of a severe bleeding phenotype (i.e. joint bleed), together with the minimization of immunological danger signals, could reduce the incidence of inhibitor formation in PUPs with severe and moderately severe hemophilia A to 15% or less. Methods The EPIC study was a Phase 3b, prospective, single arm, historically-controlled, international multicenter study to assess the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A during the first 50 exposure days (EDs) of treatment with ADVATE starting with a once-weekly, low-dose (ADVATE 25 IU/kg once weekly), prophylactic regimen. If clinically indicated, it was permissible to increase the frequency of dosing to 2 or 3 times per week. In addition, infusions during the first 20 EDs had to be given 3 to 4 days before or after any vaccinations, which had to be given subcutaneously, not intramuscularly; infusions had to be avoided if the subject had high fever (above 38°C [100°F]). Main enrolment criteria were: severe and moderately severe hemophilia A (FVIII ≤2%), age <1 year, ≤3 EDs to any FVIII-containing product used for treatment of minor bleeds or for precautionary infusions following injury, adequate venous access (without need for central venous access device), no life-threatening conditions (intracranial hemorrhage, severe trauma) or requirement for surgery at the time of enrollment, no evidence of inhibitor ≥0.6 BU in Nijmegen-modified Bethesda assay at study start, no hemostatic defect other than hemophilia A, no clinically significant chronic disease other than hemophilia A,. Information about type of FVIII gene defect was obtained in 17 subjects. FVIII inhibitor tests were performed at screening, at study infusion #3, 6, 10, 15, 20, 30, 40, and 50, and at any other time point if an inhibitor was suspected. Positive inhibitor testing had to be confirmed by 2 positive inhibitor tests on samples drawn at least 1 week apart. Results A total of 22 subjects were enrolled in the study. Of 20 subjects who met all entry criteria, 19 received treatment; of these, all had severe hemophilia A (FVIII<1%). At study entry 11 of these 19 patients were never exposed to FVIII before (PUPs), while the remaining 8 patients had been treated with FVIII concentrates before. FVIII gene mutation analysis revealed intron 22 inversions in 8 out of 17 subjects, hemizygous missense mutations resulting in a stop-codon in 2 subjects, frame-shift mutations in 2 subjects, and hemizygous missense mutations in 5 subjects. A total of 8 subjects developed a confirmed inhibitor: 2 of these 8 subjects had only borderline positivity at inhibitor testing (never above 0.6 BU) with absence of any anti-FVIII antibodies (IgG, IgA, IgM and IgG subclasses) as tested by ELISA. Thus incidence of inhibitors >0.6 BU in PUPs were 27%. A total of 67 major protocol deviations (PD) were reported in 15 patients: 44 PDs of these were reported in 10 subjects and were related to the treatment regimen and therefore have contrasted with the protocol intention, which was to minimize immunological danger signals and low dose prophylactic regimen. As a result of the observed inhibitor incidence the study was terminated based on futility analysis, i.e. the probability to achieve the primary end-point of inhibitor rate reduction to ≤15%. Details on inhibitor patients will be presented. Discussion The EPIC study showed no safety issue as confirmed by the Data Safety Monitoring Board. To align treatment decisions in the presence of danger signals (which are not completely avoidable in children around 1 year of age) with a demanding study protocol was found to be challenging. Thus the hypothesis that an early low dose prophylaxis in the absence of immunological danger signals might reduce inhibitor incidence in PUPs with hemophilia A could neither be verified nor disproved within this study. Disclosures: Auerswald: Novo Nordisk: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kurnik:Baxter: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Blatny:Baxter: speaker fee Other. Reininger:Baxter Innovations GmbH: Employment.

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Real World Use of Extended Half-Life Products and the Impact on Bleeding Events and Joint Health in the United States

Blood ◽

10.1182/blood-2018-99-113956 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1195-1195 ◽

Cited By ~ 1

Author(s):

Lynn M. Malec ◽

Char M Witmer ◽

Julie Jaffray ◽

Peter A. Kouides ◽

Kristina M. Haley ◽

...

Keyword(s):

Board Of Directors ◽

Real World ◽

Research Funding ◽

Hemophilia A ◽

Advisory Board ◽

Hemophilia B ◽

Severe Hemophilia ◽

Bleeding Events ◽

On Demand ◽

Joint Health

Abstract Background : The hemophilia treatment landscape has evolved substantially in the last several years with the approval of extended half-life (EHL) products which reduce the burden of prophylaxis. Data reported from the American Thrombosis and Hemostasis Network (ATHN) as of June 2017 indicate that 21% of patients with moderate or severe hemophilia A, and 42% of patients with moderate or severe hemophilia B, receive prophylaxis utilizing an EHL. As new treatments become available and are adopted into practice, it is important to recognize the need for evaluation of efficacy, safety, and economic impact of their use outside of the clinical trial setting. We aimed to characterize the real world impact of EHL products by collecting detailed information on bleeding rates, joint health and quality of life amongst patients cared for at ATHN-affiliated Hemophilia Treatment Centers. We hypothesized that use of EHL products were utilized in at least 30% of patients and would lead to decreased ABRs and improved joint health. To date 67 of a planned 135 subjects have been enrolled, constituting this interim analysis. Methods:Subjects were recruited from seven U.S. Hemophilia Treatment Centers. Subjects with severe hemophilia A or B ≤ 30 years of age on prophylaxis or demand therapy were eligible for enrollment. Subjects excluded from study were those with a recent joint bleed (within the last 2 weeks) or those unwilling to complete all elements of the study. Data were collected during a one-time encounter concurrent with an appointment for clinical evaluation, including demographic information, treatment regimen, product type, frequency, location and severity of all bleeds, Hemophilia Joint Health Scores (HJHS), and Quality of life (QoL). Bleeding rates in subjects receiving prophylaxis were compared with those receiving on demand therapy by type treatment, EHL vs standard half-life (SHL), and by hemophilia type. Severity of bleeding events (mild, moderate, or severe) and HJHS were compared by prophylaxis groups. Results: A total of 67 patients were enrolled and eligible for analysis. This included 58 subjects with severe hemophilia A, and 9 subjects with severe hemophilia B. The mean age of the cohort was 15 years (median 12 years, IQR 8 - 21 years). For these patients whose race information was known, 89.1% were Caucasian, 3.3% African-American, 3.3% Asian, and 4.7% were of mixed or 'other' race. Eleven out of 61 (18.0%) subjects with known ethnicity were Hispanic. Among 59 patients whose treatment type were available, the majority were on prophylaxis (n=53; 89.8%) as compared to on demand therapy (n=6; 10.2%). The average annualized bleeding rate (ABR) was 2.8 amongst all individuals. As expected, the ABR was substantially lower in those receiving prophylaxis (ABR=1.0) as compared to on demand therapy (ABR=18.6) (p<0.001). Additionally, HJHS in those receiving prophylaxis was lower (mean HJHS= 3.9), meaning less evidence of joint damage, than in those receiving demand therapy (mean HJHS= 8.8) (p=0.162). For patients with severe hemophilia A, the ABR was lower in those individuals receiving EHL (ABR= 0.5) versus SHL (ABR= 1.5), although this did not reach statistical significance (p=0.136). All subjects with severe hemophilia B enrolled to date receive EHL products (n=9) therefore no comparison of ABR could be made between EHL and SHL products; the ABR in this group was 0.9. In patients with severe hemophilia A, there was a higher HJHS for those receiving EHL (mean HJHS= 7.0) versus those receiving SHL (mean HJHS = 2.1) (p=0.053). For patients with severe hemophilia B, all of whom received EHL, the mean HJHS was lower than in the hemophilia A cohort (mean HJHS=1.2). Conclusions: We report real-world bleeding events and joint health in patients with severe hemophilia A and B utilizing EHL and SHL products across a wide U.S. geographic distribution. As anticipated, there is substantial bleed reduction with prophylaxis versus on demand therapy. In our severe hemophilia A cohort, the ABR for patients receiving EHL products was similar to ABRs reported in clinical trials, suggesting clinical trial data may be reflective of real world use. Patients with severe hemophilia A receiving EHL for prophylaxis had a lower ABR than those receiving SHL, although the early impact is not reflected in the HJHS score. Longer follow-up will be necessary to determine the impact of EHL on HJHS. Disclosures Malec: Bioverativ: Research Funding; Bayer: Consultancy; Bioverativ: Consultancy; Shire: Consultancy. Jaffray:Octapharma: Consultancy; Bayer: Consultancy; CSL Behring: Consultancy, Research Funding. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Sidonio:Octapharma: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board; Kedrion: Research Funding; Biomarin: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board. Abshire:CSL: Consultancy; Shire: Consultancy; Novo Nordisk: Other: DSMB. White:Asklepios: Other: Scientific Advisory Board; Novo Nordisk: Consultancy; Shire: Other: Physician Leadership Group; Bayer: Other: GRAC; Bioverativ: Other: DSMB; Biomarin: Other: DSMB; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Ragni:CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Bioverativ: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

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Incidence of Inhibitors in a Previously Untreated Patients with Severe Hemophilia Α Cohort Treated with a Single Third-Generation Recombinant Factor VIII Concentrate

Blood ◽

10.1182/blood-2018-99-119754 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1211-1211

Author(s):

Alessandra N L Prezotti ◽

Monica H Cerqueira ◽

Marilia Renni ◽

Clarissa Ferreira ◽

Ieda S. Pinto ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

High Titer ◽

Severe Bleeding ◽

Third Generation ◽

Severe Hemophilia ◽

Advisory Committees ◽

Inhibitor Development ◽

African Descendants

Abstract Introduction: One of the most important complications in the treatment of patients with hemophilia A is the formation of neutralizing antibodies (inhibitors) interfering in the coagulant activity of factor VIII (FVIII). The presence of inhibitor causes a direct impact on mortality and morbidity in these patients and considerably increases the cost of treatment. Among the non-genetic risk factors for inhibitor development, the influence of the type of factor concentrate used in replacement therapy (recombinant or plasma-derived) remains controversial. Thus, the evaluation of an additional population in the real world setting may contribute to elucidate this problem. Since August 2013, almost all previously untreated patients (PUPs) with hemophilia A in Brazil have been receiving exclusively the same third-generation recombinant FVIII (rFVIII) (Advate®, Shire). Objective: The aim of this study is to evaluate the immunogenicity of rFVIII (Advate®). In this context, we analyzed the occurrence of inhibitor among severe and moderately severe hemophilia A PUPs during the first 50 exposure days (EDs) to Advate®. Methods: This is an open-label, multicenter, prospective/retrospective, uncontrolled, observational study conducted in eight reference hemophilia treatment centers from distinct geographic areas in Brazil. The inclusion criteria were (a) diagnosis of severe or moderately severe hemophilia A (FVIII:C <2 IU/dL), (b) absence of previous exposure to other FVIII concentrates, except a maximum of 5 previous exposures to any blood components (whole blood, fresh-frozen plasma, packed red cells, platelets, or cryoprecipitate), and (c) exclusive treatment with Advate® until the 50th ED or until inhibitor development (primary endpoint). Positive inhibitor was defined as at least two consecutive plasma samples with Bethesda-Nijmegen assay results ≥0.60 BU/mL. Patients were considered as having low-titer inhibitors when peak titers were <5 BU/mL, and high-titer inhibitors if inhibitor titer was ≥5 BU/mL on at least one occasion. Any clinical information considered relevant for the risk of inhibitor development was analyzed when available, and included family history of inhibitor, F8 genotype, ethnicity (defined according physical traits and ancestry ethnic background in the last three generations), age at first rFVIII exposure, treatment regimens (prophylaxis or episodic), doses, occurrence of a severe bleeding episode, surgery, and use of FVIII concentrate simultaneously to infection or vaccination. Results: So far, 122 patients were enrolled, and 100 patients reached the 50th ED to rFVIII or developed inhibitor. Twenty-two are still on Advate® and have not achieved 50EDs (7 patients: 20 to 50EDs; 15 patients: <20ED). Overall, the median age at first exposure to Advate® was 11.9 months (interquartile range (IQR): 7.5-16.7), and most patients were African-descendants (48%), followed by Caucasians (45%). Positive inhibitor was detected in 35 of the 100 patients (35%), and 71% occurred during the first 20EDs. Most inhibitors were detected during prophylactic treatment (29 of 35; 82.9%). Twenty-five (25%) patients had high-titer inhibitor. Although not statistically significant, 19/48 (39.6%) of the African-descendants patients developed inhibitor, in contrast to 15/45 (33%) of the Caucasians. Interestingly, inhibitor was detected in only 1/7 (14.6%) of the patients with the indigenous background (native population). The influence of other risk factors, as severe bleeding episodes, presence of infection, surgery and history of blood transfusion, were not statistically significant. Conclusions: Overall inhibitor development in this cohort is consistent with results reported in other PUP studies with recombinant products. The majority of inhibitors developed during the first 20EDs. However, no other risk factor as intensive treatment was statistically significant, due to the small number of events observed. Although observational studies have limitations to assess the immunogenicity of FVIII products, our study contributes to this knowledge, since it evaluates a single third-generation rFVIII in a distinct population, with similar access to factor concentrate and same treatment regimen. Disclosures Prezotti: Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bioverative: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Medina:Shire: Speakers Bureau. Ozelo:Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; BioMarin: Honoraria, Speakers Bureau; Shire: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Honoraria, Research Funding; Grifols: Honoraria.

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Phase 4 Safety and Efficacy Study of Antihemophilic Factor (Recombinant) in Previously Treated Chinese Patients With Severe/Moderately Severe Hemophilia A

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029621989811 ◽

2021 ◽

Vol 27 ◽

pp. 107602962198981

Author(s):

Yongqiang Zhao ◽

Yu Hu ◽

Jie Jin ◽

Xielan Zhao ◽

Xuefeng Wang ◽

...

Keyword(s):

Hemophilia A ◽

Bleeding Event ◽

Chinese Patients ◽

Severe Hemophilia ◽

Bleeding Events ◽

Safety And Efficacy ◽

On Demand ◽

Previously Treated ◽

Hemostatic Efficacy ◽

Antihemophilic Factor

Antihemophilic factor (recombinant) (rAHF; ADVATE®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) is indicated for the treatment and prevention of bleeding in patients with hemophilia A. We aimed to assess the safety and efficacy of standard prophylaxis versus on-demand treatment with rAHF in previously treated Chinese patients with severe/moderately severe hemophilia A. This open-label, sequential, interventional, postapproval study (NCT02170402) conducted in China included patients of any age with hemophilia A with factor VIII (FVIII) level ≤2%. Patients received 6 months’ on-demand rAHF then 6 months’ rAHF prophylaxis (20-40 IU/kg every 48 ± 6 hours). The primary objective was percentage reduction in annualized bleeding rate (ABR) in the per-protocol analysis set (PPAS); secondary objectives included ABR by bleeding subtype, hemostatic efficacy, immunogenicity, and safety. Of 72 patients who received ≥1 rAHF dose, 61 were included in the PPAS. Total ABR was lower during prophylaxis (mean 2.5, 95% CI 1.5-3.7; median 0) versus on-demand treatment (mean 58.3, 95% CI 52.5-64.7; median 53.9), representing a 95.9% risk reduction. Similar findings in favor of prophylaxis were observed for all types of bleeding event by cause and location. rAHF hemostatic efficacy was rated as “excellent”/“good” in 96.1% of treated bleeding events. Transient FVIII inhibitors (0.6-1.7 BU) in 4 patients resolved before study end; no unexpected safety issues were observed. rAHF prophylaxis in this study of previously treated Chinese patients with severe/moderately severe hemophilia A resulted in a clear reduction in bleeding events versus rAHF on-demand treatment, with no change in safety profile.

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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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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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Safety and Efficacy of Turoctocog Alfa in Prevention and on-Demand Treatment of Bleeding Episodes in Patients with Hemophilia A

Blood ◽

10.1182/blood.v128.22.3790.3790 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3790-3790

Author(s):

Dragana Janic ◽

Irina Matytsina ◽

Mudi Misgav ◽

Johannes Oldenburg ◽

Margareth C Ozelo ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Open Label ◽

Main Trial ◽

Safety And Efficacy ◽

Safety Concerns ◽

On Demand ◽

Prevention And Treatment

Abstract Background Turoctocog alfa is a B-domain truncated recombinant factor VIII (rFVIII) product for the prevention and treatment of bleeds in patients with hemophilia A. The ongoing guardian™2 trial using turoctocog alfa consists of a main trial with planned visits, a surgery subtrial for patients who need to undergo surgery during the main trial, and an on-demand subtrial based on a regulatory requirement to collect data for at least 10 patients treated on-demand for 6 months. The guardian™2 trial is an open-label, prospective, international extension to pivotal trials in adults and adolescents (aged 12-65 years; guardian™1) and children (aged <12 years; guardian™3). Patients who completed the pharmacokinetic trials (NN7008-3600, NN7008-3893, or NN7008-4015), and new patients involved in the on-demand subtrial, also participated in guardian™2. We report an analysis of new long-term safety and efficacy data from the main guardian™2 trial and on-demand subtrial of turoctocog alfa. Methods Male patients with severe hemophilia A (FVIII ≤1%) without inhibitors (<0.6 Bethesda units [BU]) were enrolled from 19 countries. Turoctocog alfa was used prophylactically (20-50 IU/kg every second day or 20-60 IU/kg three times weekly) and on-demand (20-200 IU/kg/day) to treat bleeds. The primary safety endpoint was inhibitor development (≥0.6 BU/mL). All adverse events were reported. The main efficacy endpoints included hemostatic success when treating bleeds (excluding patients with missing evaluations), number of turoctocog alfa infusions required to stop bleeds, annualized bleeding rate (ABR), and consumption of turoctocog alfa. Safety and efficacy were assessed at the interim cut-off date, March 25, 2015. Results Prophylaxis and on-demand treatment were received by 199 and 19 patients, respectively (equivalent to 589 and 12.5 years of exposure to turoctocog alfa, respectively). Turoctocog alfa was used to treat 1508 bleeds in 162 patients receiving prophylaxis, and for 320 bleeds in 19 patients receiving on-demand treatment. No FVIII inhibitors, hypersensitivity, allergic reactions, or other safety concerns were reported in the main trial or on-demand subtrial for any patients. Treatment of bleeds was successful ('excellent' or 'good' response) in 90% of patients receiving prophylaxis and in 97% of those treated on-demand; the overall proportion of bleeds stopped with 1-2 injections was 90.7%, and 95.7% taking up to three injections. The median ABR (bleeds/patient/year) was 1.48 (mean Poisson estimated ABR: 2.56) for patients treated prophylactically, and 30.3 (mean Poisson estimated ABR: 25.56) for patients treated on-demand. Mean turoctocog alfa consumption (IU/kg/year/patient) was 5335 for patients on prophylaxis and 1707 for patients treated on-demand. Mean prophylactic dose was 32 IU/kg. Mean dose for treatment of bleed from start to stop was 61 IU/kg for patients on prophylaxis and 44 IU/kg for patients treated on-demand. Conclusion The latest data from the ongoing guardian™2 trial demonstrate the long-term safety and efficacy of turoctocog alfa for the prevention and treatment of bleeds in patients with severe hemophilia A. No FVIII inhibitors or other safety concerns have been reported. Compared with on-demand treatment, prophylaxis resulted in ~3-fold higher consumption of turoctocog alfa, and a 90% reduction in bleed rates. Disclosures Janic: Pfizer: Other: Paid Instructor, Research Funding; Bayer: Other: Paid Instructor, Research Funding; Baxter: Other: Paid Instructor, Research Funding; Novo Nordisk: Other: Paid Instructor, Research Funding; Octopharma: Research Funding. Matytsina:Novo Nordisk: Employment. Misgav:Novo Nordisk: Speakers Bureau. Ozelo:Bayer: Research Funding; Baxter: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Research Funding; Biogen: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau. Recht:Kedrion: Consultancy; Biogen Idec: Research Funding; Novo Nordisk: Consultancy, Research Funding; Baxalta: Research Funding. Korsholm:Novo Nordisk: Employment, Equity Ownership. Savic:Novo Nordisk: Other: Investigator. Santagostino:Novo Nordisk: Consultancy; Pfizer: Consultancy; Grifols: Consultancy; Sobi: Consultancy; Baxalta: Consultancy; Roche: Consultancy; CSL Behring: Consultancy; Kedrion: Consultancy; Octapharma: Consultancy; Biogen Idec: Consultancy; Bayer: Consultancy.

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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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F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis

Blood ◽

10.1182/blood-2011-09-379453 ◽

2012 ◽

Vol 119 (12) ◽

pp. 2922-2934 ◽

Cited By ~ 195

Author(s):

Samantha C. Gouw ◽

H. Marijke van den Berg ◽

Johannes Oldenburg ◽

Jan Astermark ◽

Philip G. de Groot ◽

...

Keyword(s):

Systematic Review ◽

Gene Mutation ◽

Hemophilia A ◽

High Titer ◽

Meta Analysis ◽

Gene Mutations ◽

Secondary Outcome ◽

Missense Mutations ◽

Severe Hemophilia ◽

Inhibitor Development

Abstract This systematic review was designed to provide more precise effect estimates of inhibitor development for the various types of F8 gene mutations in patients with severe hemophilia A. The primary outcome was inhibitor development and the secondary outcome was high-titer-inhibitor development. A systematic literature search was performed to include cohort studies published in peer-reviewed journals with data on inhibitor incidences in the various F8 gene mutation types and a mutation detection rate of at least 80%. Pooled odds ratios (ORs) of inhibitor development for different types of F8 gene mutations were calculated with intron 22 inversion as the reference. Data were included from 30 studies on 5383 patients, including 1029 inhibitor patients. The inhibitor risk in large deletions and nonsense mutations was higher than in intron 22 inversions (pooled OR = 3.6, 95% confidence interval [95% CI], 2.3-5.7 and OR = 1.4, 95% CI, 1.1-1.8, respectively), the risk in intron 1 inversions and splice-site mutations was equal (pooled OR = 0.9; 95% CI, 0.6-1.5 and OR = 1.0; 95% CI, 0.6-1.5), and the risk in small deletions/insertions and missense mutations was lower (pooled OR = 0.5; 95% CI, 0.4-0.6 and OR = 0.3; 95% CI, 0.2-0.4, respectively). The relative risks for developing high titer inhibitors were similar.

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