Athn 16: Safety of Coagulation Factor VIIa (recombinant)-Jncw for the Treatment of Bleeding Events in Patients with Congenital Hemophilia a or B with Inhibitors with or without Prophylactic Treatment

Abstract Background: A new recombinant activated factor VII, eptacog beta (SEVENFACT®, rFVIIa-jncw) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of bleeding events (BEs) in individuals >12 years of age with hemophilia A or B (HAB) with inhibitors. In the eptacog beta phase III trial (Wang, Haemophilia, 2017), 87% of BEs were successfully treated using two different dosing regimens within 12 hours of bleeding onset. In two studies looking at the safety of eptacog beta Ducore, Haemophilia, 2017), a total of 11 treatment-emergent adverse events (TEAEs) were reported in 42 participants, all mild and transitory. To date, no studies designed to assess safety of treatment of breakthrough BEs in people on emicizumab with eptacog beta have been performed. Objective: To evaluate the safety of eptacog beta when used to treat BEs in participants with HAB with inhibitors with or without prophylactic treatment. Methods: ATHN 16 (NCT04647227) is a phase IV, United States-centric multi-center, open-label safety study enrolling participants with HAB with inhibitors aged 12 to 65 years, inclusive, who are either on long-term prophylactic treatment (e.g., emicizumab) at risk of experiencing a breakthrough BE or who are not on prophylactic treatment who may need to control a BE. Exclusion criteria include any bleeding disorder in addition to HAB, a known hypersensitivity to eptacog beta or rabbit proteins, or the inability to provide informed consent. The maximum study duration for any participant in the study is up to 2 years from the time of enrollment. We plan to enroll between 28 to 55 participants with the goal of collecting data on 100 BEs. Safety of eptacog beta will be evaluated based on events included in the European Haemophilia Safety Surveillance (EUHASS) protocol, including allergic or other acute events, treatment-emergent side effects, transfusion-transmitted infections, inhibitor development, thrombosis, cardiovascular events, malignancies, neurological events, and death. After signed informed consent is obtained, demographics, bleeding disorder history, inhibitor history, baseline medical and surgical history for the 6-month period before the baseline visit will be captured. Each participant will receive nine 75 µg/kg doses of eptacog beta supplied by the study funder. Eptacog beta will be administered at the time of a BE by the participant or by study staff; the dose and duration of treatment will be determined at the discretion of the treating physician. BE details such as timing, any treatments associated with the BE (including eptacog beta), and timing of resolution of the BE will be collected as well as surgical procedures and all AEs and serious AEs. Results: At the time of abstract submission, ATHN 16, having received central IRB approval, is being rolled out across the United States Hemophilia Treatment Center Network. There are a total of 20 sites where the protocol will be conductedalex. We plan to report participant demographics, BE details, as well as all safety data meeting the EUHASS endpoints. In addition, we will report any pregnancies as AEs of special interest. All serious AEs will also be reported. The ATHN 16 Safety Analysis Set is defined as all participants who received at least a single dose of eptacog beta. Baseline characteristics will be summarized using descriptive statistics for continuous variables, and frequencies and percentages for categorical variables. The number and percentage of participants with treatment-emergent AEs (TEAEs), serious AEs (SAEs), serious TEAEs, and treatment-related TEAEs (i.e., adverse drug reactions) will be presented for all participants. The number and percentage of participants with TEAEs and/or allergic and anaphylactic reactions will be presented for all participants. There are no pre-specified efficacy endpoints. Conclusions: ATHN 16 will explore the safety of eptacog beta as therapy for BEs in participants with HAB complicated by inhibitors with or without concurrent prophylactic treatment. As the first interventional study sponsored by ATHN, ATHN 16 represents a crucial step forward in ATHN's clinical research capabilities. Disclosures Chrisentery-Singleton: CSL Behring: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; HEMA Biologics: Consultancy, Honoraria; Novo Nordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Pfizer: Consultancy; Sanofi: Consultancy; Spark: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Kedrion: Consultancy; Biomarin: Speakers Bureau; Global Blood Therapeutics: Speakers Bureau; Bayer: Honoraria; BPL Plasma: Honoraria. Alexander: HEMA Biologics: Consultancy, Ended employment in the past 24 months; Johnson & Johnson: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Roche/Genentech: Current equity holder in publicly-traded company. Al-Sabbagh: LFB: Current Employment. Bonzo: LFB: Current Employment. Callaghan: Kedrion: Consultancy; Biomarin: Consultancy; Spark: Consultancy; uniQure: Consultancy; Global Blood Therapeutics: Consultancy, Speakers Bureau; Pfizer: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy, Speakers Bureau; Alnylum: Current equity holder in publicly-traded company; Hema Biologics: Consultancy; Forma: Consultancy; Chesei: Consultancy; Agios Pharmaceuticals: Current Employment. Giermasz: Bayer: Consultancy; ATHN: Consultancy; NovoNordisk: Consultancy; UniQure: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; Sangamo Therapeutics,: Research Funding; Pfizer: Consultancy; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding. Journeycake: LFB: Honoraria; HEMA Biologics: Honoraria. Nasr: HEMA Biologics: Consultancy. Quon: Orthopaedic Institute for Children: Current Employment. Recht: uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; American Thrombosis and Hemostasis Network: Current Employment; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Oregon Health & Science University: Current Employment.

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Bleeding Events and Safety Outcomes in Patients with Hemophilia a with Inhibitors: A Prospective, Multicenter, Non-Interventional Study

Blood ◽

10.1182/blood.v128.22.3800.3800 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3800-3800 ◽

Cited By ~ 1

Author(s):

Johnny Mahlangu ◽

Johannes Oldenburg ◽

Michael U Callaghan ◽

Midori Shima ◽

Elena Santagostino ◽

...

Keyword(s):

Research Funding ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Interventional Study ◽

Bleeding Events ◽

Legal Guardian ◽

Phase 3 ◽

Advisory Committees ◽

Safety Outcomes ◽

Bypassing Agents

Abstract Introduction: Coagulation factor VIII (FVIII) deficiency in hemophilia A (HA) patients (pts) results in spontaneous bleeding events, secondary arthropathy and diminished quality of life (QoL). FVIII replacement agents, the current standard of care, may require several infusions to treat bleeding events and infusions 2-3 times a week are needed for prevention of bleeding events due to relatively short half-lives. A major challenge of current therapies is development of anti-FVIII alloantibodies (inhibitors), which occur in 15-30% of HA pts, diminish effectiveness of FVIII replacement and are associated with significant morbidity and reduced QoL. Options for pts with inhibitors are limited. Bypassing agents to prevent/treat bleeding events, and immune tolerance induction to eliminate inhibitors, require frequent dosing, are not available in all countries, and have suboptimal efficacy. Thus, a high unmet need exists for safe, more effective and less burdensome options for pts with inhibitors. Emicizumab (ACE910), a bispecific monoclonal antibody in development for the management of HA, binds to FIXa and FX to mimic FVIII cofactor function and may be able to address current treatment needs. Real world data (RWD) collected from HA pts are considered of high importance for the emicizumab clinical development program, providing the possibility of intra-patient comparison for those who may be subsequently eligible to participate in a pivotal emicizumab Phase 3 study (NCT02622321). This non-interventional study (NIS) aims to prospectively collect detailed, high-quality data on bleeding events and safety outcomes in HA pts treated according to local routine clinical practice. In the first cohort (Cohort A), data from adult/adolescents with inhibitors were collected. Methods: This prospective NIS (NCT02476942) was approved by local Ethics review groups, and all pts and/or legal guardians signed informed consent/assent prior to study entry. In Cohort A, eligible pts were ≥12 years old and had congenital HA of any severity; documented history of high-titer FVIII inhibitors (≥5 Bethesda Units/mL); documented treatment with bypassing agents for ≥6 months; and, ≥6 or ≥2 bleeds in the last 6 months on episodic or prophylactic treatment, respectively. Primary objective was to characterize the number of bleeding events over time. Bleeding/bypassing agent data were collected through a bleed and medication questionnaire (BMQ) developed by the Sponsor, as no standard questionnaire is available. BMQ was completed by the pt/legal guardian via an electronic handheld device. Demographic data and medical history were collected from pts' medical records on an electronic Case Report Form. Throughout the study, investigators recorded adverse events (AEs), concomitant medication, and routine laboratory assessment data. At least monthly interactions of pts/legal guardian with a professional from their treatment center were requested to confirm self-reported bleed/medication information. Results: 103 HA pts with inhibitors (75 on episodic and 28 on prophylactic regimens with bypassing agents) from 33 centers and 12 countries were enrolled in Cohort A. As of 7/21/16, 54 pts had rolled over to the emicizumab Phase 3 study in adults/adolescents with inhibitors. The following Cohort A data will be presented: pt demographics/characteristics; global distribution of pts by country; summary of hemophilia medical history, concomitant medications and surgeries; pts' self-reported information on bleeding events and treatment (all, and by episodic and prophylactic treatment), including bleeding rates, types and locations, reason for coagulation product use, product type used, dose; and, safety. Conclusion: The NIS will provide high quality documentation of bleeding events and safety outcomes in adult/adolescent HA pts with inhibitors treated with bypassing agents according to local clinical practice. For those participating in the ongoing Phase 3 emicizumab study, these data will provide the opportunity to perform robust intra-patient comparisons of prospectively collected bleeding event/medication data before and during emicizumab treatment. This is the first report of prospective RWD being collected for use as a valid historical control for a pivotal Phase 3 study in HA pts with inhibitors, and a novel and unique approach to bolster data reported in the clinical development of emicizumab. Disclosures Mahlangu: Bayer: Research Funding, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Amgen: Speakers Bureau; Biotest: Speakers Bureau; Baxalta: Consultancy. Callaghan:Grifols: Honoraria; Bayer: Honoraria; Baxalta: Honoraria, Research Funding; Roche: Honoraria, Research Funding; CSL Behring: Honoraria; Biogen: Honoraria. Shima:F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sysmex Corporation: Patents & Royalties, Research Funding. Santagostino:Bayer: Consultancy; Grifols: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Octapharma: Consultancy; CSL Behring: Consultancy; Baxalta: Consultancy; Pfizer: Consultancy; Biogen Idec: Consultancy; Sobi: Consultancy; Roche: Consultancy. Lehle:Roche: Employment. Uguen:Roche: Employment. Hirst:F. Hoffmann La-Roche Ltd: Employment; AstraZeneca: Other: Previous employment . Recht:Novo Nordisk: Consultancy, Research Funding; Biogen Idec: Research Funding; Baxalta: Research Funding; Kedrion: Consultancy. Kruse-Jarres:Pfizer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria; Bayer: Consultancy, Honoraria.

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Effect of Moderate and Severe Hemophilia a on Daily Life in Children and Their Caregivers: A CHESS Paediatrics Study Analysis

Blood ◽

10.1182/blood-2020-134658 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-45

Author(s):

Kate Khair ◽

Francis Nissen ◽

Mariabeth Silkey ◽

Tom Burke ◽

Aijing Shang ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Disease Burden ◽

Hemophilia A ◽

Daily Life ◽

Social Activity ◽

Publicly Traded ◽

Advisory Committees ◽

Lost Work ◽

Hours Of Work

Introduction: Hemophilia A (HA) is a congenital bleeding disorder, caused by a deficiency in clotting factor VIII (FVIII) and characterized by uncontrolled bleeding and progressive joint damage. This analysis assesses the impact of disease burden on the daily life of children with hemophilia A (CwHA) and their caregivers, addressing a deficit of current research on this topic. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey in a Paediatric Population (CHESS Paediatrics) is a retrospective, burden-of-illness study in children with moderate and severe HA (defined by endogenous FVIII [IU/dL] relative to normal; moderate, 1-5%; severe, <1%) across France, Germany, Italy, Spain and the UK. CwHA were recruited and stratified by both age group (0-5 years:6-11 years:12-17 years=1:1:1) and disease severity (severe:moderate=approximately 2:1, prioritizing children with severe HA [CwSHA]). Data for this analysis were captured from physicians, children, and their caregivers. Physicians completed online case report forms for treated children, and the child and/or their caregivers completed a paper-based questionnaire utilizing 5-point Likert scales. For CwHA aged 0-7, the questionnaire was completed by the caregiver, while for CwHA aged 8-17, children and caregivers completed different sections. Hours of care provided by the caregiver and work lost by the caregiver were reported as median values due to non-normal data distribution. Informed consent was obtained for all participants. Upon review, the study was approved by the University of Chester ethical committee. Results: Data from child/caregiver questionnaires were available for 196 CwHA (moderate, 25.5%; severe, 74.5%); the majority of these children, as expected, were receiving prophylaxis (72.4%), and did not have FVIII inhibitors (89.8%; Table 1). There was a direct impact of disease burden on CwHA, particularly with regard to physical and social activities (Figure 1). Overall, it was agreed or strongly agreed by the child or caregiver that 48.0% and 57.5% of children with moderate HA (CwMHA) and CwSHA respectively, have reduced physical activity due to HA, and 46.0% and 57.5%, respectively, have reduced social activity due to HA. A total of 36.0% and 61.0% of CwMHA and CwSHA, respectively, had adapted their treatment in anticipation of physical or social activity (Table 1). Furthermore, 34.0% of CwMHA and 55.4% of CwSHA were frustrated due to their disease, and many (CwMHA, 36.0%; CwSHA, 50.7%) felt that they had missed opportunities (Figure 1). For 66.0% of CwMHA and 76.0% of CwSHA, it was reported that their daily life was compromised due to their HA. Caregivers provided a median (interquartile range [IQR]) of 19.0 (10.0-59.5) and 12.0 (5.0-20.0) hours a week of care for the hemophilia-related needs of their CwMHA (n=30) or CwSHA (n=105), respectively. Of those who responded, 17.4% (n=4/23) and 25.0% (n=20/80) of caregivers to CwMHA or CwSHA, respectively, stated they have lost work due to their caregiving duty. This was more than twice as common for caregivers in families with multiple CwHA (42.9%, n=9/21 responses) compared with those in families with one CwHA (18.5%, n=15/81 responses). Median (IQR) hours of work per week estimated to be lost were 20.0 (17.0-22.0) for caregivers of CwMHA (n=4) and 12.5 (4.50-20.0) for caregivers of CwSHA (n=20). Conclusions: In conclusion, both children and caregivers make sacrifices in their daily lives due to HA; many CwHA reported reduced physical and social activities, fewer opportunities and feelings of frustration due to their HA. Caregivers reported spending a significant number of hours caring for their child and some reported losing work due to their caring responsibilities. However, some outcomes may be limited by the small number of respondents and narrow response options, particularly those regarding the caregiver burden. Responses on the hours of work lost may be subject to selection bias, as caregivers who have lost work may be more likely to respond to this question. Additionally, as this question is targeted at caregivers in employment, it is unknown if some caregivers have left employment due to their caregiving responsibilities. According to this analysis, children/caregivers are frequently required to adapt the child's treatment before the child engages in activities. Overall, the burden of disease was similar in children with moderate and severe HA. Disclosures Khair: Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Haemnet: Membership on an entity's Board of Directors or advisory committees. Nissen:GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Silkey:Aerotek AG: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Burke:HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Shang:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Noone:Research Investigator PROBE: Research Funding; Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees.

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Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽

10.1182/blood-2019-126659 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1126-1126

Author(s):

Karen L. Zimowski ◽

Glaivy M. Batsuli ◽

Paulette Bryant ◽

Jenny McDaniel ◽

Kelly Tickle ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Severe Bleeding ◽

Severe Hemophilia ◽

Bleeding Events ◽

Advisory Committees ◽

Acute Bleeding ◽

Fviii Activity ◽

Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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Human-Cl Rhfviii Effectively and Safely Prevents Bleeding Episodes in Previously Treated Adult Patients with Severe Haemophilia A

Blood ◽

10.1182/blood.v120.21.1132.1132 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1132-1132

Author(s):

Sigurd Knaub ◽

Toshko Lissitchkov ◽

Kingsley Hampton ◽

Mario Von Depka ◽

Savita Rangarajan ◽

...

Keyword(s):

Gene Therapy ◽

Research Funding ◽

Prophylactic Treatment ◽

Hemophilia A ◽

Haemophilia A ◽

Severe Haemophilia ◽

Open Label ◽

Bleeding Rate ◽

Previously Treated

Abstract Abstract 1132 The main purpose of this prospective, multi-center, open-label phase 3 study was to assess the efficacy of prophylactic treatment with Human-cl rhFVIII, the first human cell-line derived recombinant FVIII, in previously treated patients (PTPs) with severe haemophilia A. Patients were to receive 30–40 international units (IU) FVIII of Human-cl rhFVIII per kg every other day for 6 months. Efficacy of preventing and treating bleeds were judged using objective criteria taking the monthly bleeding rate and the number of infusions needed to manage a break-through bleed into account. In-vivo recovery (IVR) was determined at the beginning of the study and after 3 and 6 months. FVIII:C was measured by validated chromogenic (CHR) and one-stage (OS) assays in a central laboratory, which also assigned drug potencies. Inhibitor activity was determined using the Nijmegen modification of the Bethesda assay before the first administration and at defined intervals thereafter. Thirty-two patients between 18 and 75 years of age were enrolled from 11 centres in Europe and treated prophylactically for 6.0±0.9 months (mean ± SD) with a mean prophylactic dose of 32.8 IU/kg. Sixteen patients never bled, 11 patients bled once and 5 more than once. The mean total and spontaneous monthly bleeding rate was 0.188±0.307 and 0.095±0.211, respectively. Efficacy of the prophylactic treatment was “excellent” in all patients for spontaneous BEs and “excellent” or “good” in all patients but one for all types of bleeds. All treatments of bleeds were rated as “excellent” (71.4%) or “good” (28.6%). The IVR at baseline was 2.6±0.5 % per IU/kg for the CHR and 2.2±0.5 % per IU/kg for the OS assay and remained stable during the study. A total of 2921 infusions were given in the study. Human-cl rhFVIII was well tolerated and no patient experienced a related serious adverse event. No FVIII inhibitors were detected. Conclusion: The data indicate that Human-cl rh FVIII is safe and efficacious in preventing and treating bleeds in PTPs with severe haemophlia A. Disclosures: Knaub: Octapharma AG: Employment. Lissitchkov:Octapharma AG: PI Other. Tuddenham:College London: Consultancy, Employment, Gene therapy for hemophilia A, Gene therapy for hemophilia A Patents & Royalties, Research Funding. Collins:Octapharma AG: Consultancy. Oldenburg:d and e: Baxter, Bayer, Biotest, CSL-Behring, Grifols, Inspiration, NovoNordisk, Octapharma, Pfizer e: Biogen IDec, Swedish Orphan Biovitrum: Honoraria, Research Funding. Bichler:Octapharma AG: Employment.

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Surgical Experience from the Phase III STASEY Trial of Emicizumab Prophylaxis in Persons with Hemophilia A with FVIII Inhibitors: Final Analysis

Blood ◽

10.1182/blood-2021-145890 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 344-344

Author(s):

Giancarlo Castaman ◽

Jerzy Windyga ◽

Hazza Alzahrani ◽

Susan Robson ◽

Fabian Sanabria ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Knee Prosthesis ◽

Coagulation Factor ◽

Left Knee ◽

Phase Iii ◽

Postoperative Treatment ◽

Research Centre ◽

Case Report Form ◽

Knee Arthrodesis

Abstract Background: Emicizumab, a bispecific monoclonal antibody, bridges activated factor (F) IX and FX, replacing the function of missing activated FVIII in persons with hemophilia A (PwHA). The Phase IIIb, multicenter, single-arm STASEY study (NCT03191799) assessed the safety and efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors. Surgical experiences in STASEY are reported here. Methods: Following informed consent and ethics committee approval, PwHA aged ≥12 years with FVIII inhibitors received 3 mg/kg/week emicizumab for 4 weeks (loading dose), then 1.5 mg/kg/week for the remaining 2-year treatment period. Minor and major surgeries were managed per the investigators' discretion. The type and number of procedures performed, additional prophylaxis, and frequency and management of postoperative bleeds were analyzed. Surgeries occurring up to 28 days after the last dose of emicizumab were included, due to emicizumab's ~28-day half-life (Emicizumab Prescribing Information, United States Food and Drug Administration, 2017). Surgeries were documented using an electronic case report form by the treating physicians and classified as minor or major based on manual medical review (Santagostino, et al. Haemophilia, 2015). Bleed and prophylactic hemophilia medication data were recorded in the electronic Bleed Medication Questionnaire by participants. Case narratives were provided by trial investigators. Results: Overall, 46 patients reported ≥1 on-study surgery. Thirty-seven patients had 56 minor surgeries (central venous access device [CVAD], n=9; dental, n=20; joint, n=4; other, n=23) (Figure), one of which (skin laceration and suture insertion on Day 9) was performed during the loading phase. Twenty-four surgeries (42.9%) were managed with additional prophylactic medications (Table). Of these, 11/24 (45.8%) resulted in postoperative bleeds, of which 6/11 were treated (54.5%). Of surgeries managed without additional prophylactic medications, 15/32 (46.9%) resulted in postoperative bleeds, of which 5/15 (33.3%) were treated. A total of 13 patients had 22 major on-study surgeries (arthroplasty, n=13; other, n=9). 'Other' included hemorrhoid operations, coronarography, sigmoidectomy, colostomy, laparotomy and polypectomy. Eighteen (81.8%) major surgeries, including all arthroplasties, were managed with additional prophylactic medications (Table). Of these, 12/18 (66.7%) resulted in postoperative bleeds (including 10/13 arthroplasties), of which six (50.0%) were treated (all arthroplasties). Four (18.2%) major surgeries were managed without additional prophylactic medication, including three hemorrhoid operations in one patient, and a coronarography in a patient with acute myocardial infarction. One hemorrhoid operation resulted in a postoperative treated bleed. Major surgeries included a 55-year-old male with Grade 4 device dislocation of left knee prosthesis on Day 7, who was diagnosed with recurrent infection and prosthesis misalignment on Day 62. Amputation of the left leg above the knee was performed, with treatment including tranexamic acid and rFVIIa. A 61-year-old male with left knee prosthesis infection underwent left knee arthrodesis on Day 457, vacuum-assisted closure therapy on Day 495, skin grafting on Day 512, and left knee arthrodesis with skin flap placement on Day 527. Throughout these surgeries, the individual experienced recurrent joint bleeding and received rFVIIa. Neither of these individuals had a change in their study treatment due to these events. No thrombotic events (TEs) or thrombotic microangiopathies (TMAs) related to surgeries were observed. Conclusions: In the STASEY study of PwHA with FVIII inhibitors receiving emicizumab prophylaxis, most minor surgical procedures were performed without additional prophylactic coagulation factor and did not result in postoperative treated bleeds. Therefore, emicizumab alone provided adequate hemostatic coverage for some PwHA undergoing certain types of minor surgery, such as tooth extraction and CVAD removal. Major surgeries were safely performed with additional coagulation prophylaxis. Management of surgeries with rFVIIa did not result in TE or TMA. In case of bleeds, a bleed management plan should be in place. Effects of emicizumab on coagulation and assays may persist for up to 6 months after the last dose, which may be relevant when planning postoperative treatment. Figure 1 Figure 1. Disclosures Castaman: Uniqure: Honoraria; Bayer: Honoraria; Sobi: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Kedrion: Honoraria; LFB: Honoraria; Grifols: Honoraria; Werfen: Honoraria; Biomarin: Honoraria; Sanofi: Honoraria; F Hoffmann-La Roche Ltd: Honoraria. Windyga: Swixx BioPharma: Honoraria; Octapharma: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; Werfen: Honoraria; Bayer AG: Honoraria; Aspen: Honoraria; Alfasigma: Honoraria; Takeda: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Alnylam Pharmaceuticals: Research Funding; Sanofi/Genzyme: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Alexion: Honoraria; CSL Behring: Honoraria; Rigel Pharmaceuticals: Research Funding; Novo Nordisk: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding. Alzahrani: Sobi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; King Faisal Specialist Hospital and Research Centre: Current Employment. Robson: F. Hoffmann-La Roche Ltd: Current Employment, Ended employment in the past 24 months. Sanabria: F. Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Howard: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Jiménez-Yuste: Octapharma: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding.

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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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Problem Joints and Their Clinical and Humanistic Burden in Children and Adults with Moderate and Severe Hemophilia a: CHESS Paediatrics and CHESS II

Blood ◽

10.1182/blood-2020-140306 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Paul McLaughlin ◽

Cedric Hermans ◽

Sohaib Asghar ◽

Tom Burke ◽

Francis Nissen ◽

...

Keyword(s):

Quality Of Life ◽

Research Funding ◽

Hemophilia A ◽

Joint Damage ◽

Severe Hemophilia ◽

Publicly Traded ◽

Hemophilic Arthropathy ◽

Joint Health ◽

Humanistic Burden

Introduction Severe hemophilia A (SHA) is characterized by spontaneous (non-trauma related) bleeding episodes into the joint space and muscle tissue, leading to progressive joint deterioration and chronic pain. Chronic joint damage is most often associated with severe hemophilia, however more recent research has illustrated that people with moderate hemophilia A (MHA) also experience hemophilic arthropathy and functional impairment. The need to measure joint health in children as well as adults, is underscored by findings from the Joint Outcome Continuation Study, which found that FVIII prophylaxis was insufficient to protect joints from damage, from childhood through adolescence in severe HA (Warren et al., 2020). The objective of this analysis is to gain a more patient-centric understanding of the clinical, economic and humanistic burden associated with 'Problem Joints', a measure of joint morbidity developed in consultation with an expert panel to overcome limitations with existing measures, in people with MHA and SHA. Methods A descriptive cohort analysis was conducted, utilizing retrospective, cross-sectional real-world data from the 'Cost of Haemophilia in Europe: a Socioeconomic Survey' (CHESS Paeds and CHESS II), studies of adult and pediatric persons with hemophilia. The analysis population is comprised of children (17 and below) with MHA or SHA in CHESS Paeds, and adults aged 20 and over with MHA or SHA in CHESS II. To account for the possibility that persons aged 18 or 19 in CHESS II may have participated in CHESS Paeds, these individuals were excluded from the analysis. Physician-reported clinical outcome data and patient/caregiver-reported quality of life were analyzed. A problem joint (PJ) is defined as having chronic joint pain and/or limited range of movement due to compromised joint integrity (i.e. chronic synovitis and/or hemophilic arthropathy). Analyses were stratified by number of PJs: none, 1 PJ, and 2+ PJs. We report retrospective data of the 12 months prior to study enrollment, on annualized bleeding rate (ABR), prevalence of target joints (TJ), as defined by the International Society on Thrombosis and Haemostasis, and EQ-5D-/5L/Y/Proxy score. Results are presented as mean (standard deviation) or N (%). Results Among 785 participants (N = 464 SHA; N = 321 MHA) in CHESS Paeds, mean age and BMI were 10.33 (4.63) and 22.50 (17.07), respectively. Of 493 participants (aged 20 and above) in CHESS II (N = 298 SHA; N = 195 MHA), the mean age and BMI were 38.61 (14.06) and 24.55 (2.92), respectively. Current inhibitor to FVIII replacement was more prevalent in children than in adults (10% vs. 5%). In CHESS II, approximately 40% of people with MHA and 49% with SHA had one or more PJs, respectively [1 PJ (23% vs. 28%); 2+ PJs (16% vs. 21%)]. In CHESS Paeds, approximately 14% of children with MHA and 18% with SHA had at least one PJ, respectively [1 PJ (9% vs. 14%); 2+ PJs (5% vs. 3%)]. TJs were less prevalent with MHA in comparison to SHA, in both adults (24% vs. 45%) and children (13% vs. 22%). Clinical burden was higher among both children and adults with PJs compared to those with no PJs. ABR correlates with the number of PJs, in those with MHA and SHA in CHESS II (Figure 1). Similarly, PJs were associated with higher ABR across MHA and SHA in CHESS Paeds (Figure 2). Hemophilia-related hospitalizations were higher in both adult and pediatric participants with PJs. In CHESS II, MHA with no PJs had fewer [0.73 (1.23)] hospitalizations compared to having those with 1 PJ [1.38 (1.11)] or 2+ PJs [1.28 (1.25)]. Similarly, children with MHA with 2+ PJs had 1.60 (1.92) hemophilia-related hospitalizations, compared to 1.38 (1.92) with 1 PJ and 0.71 (1.14) with no PJs. PJs were associated with impaired quality of life. In CHESS II, MHA and SHA EQ-5D-5L values in persons with no PJs were 0.81 (0.19) and 0.79 (0.18), respectively, compared to 0.65 (0.16) and 0.62 (0.23) with 1 PJ, and 0.65 (0.14) and 0.51 (0.33) in with 2+ PJs. A similar trend was observed in EQ-5D-Y and EQ-5D-proxy scores in CHESS Paeds. Conclusions Data from CHESS Paeds and CHESS II demonstrate an association between chronic joint damage, as measured by the 'problem joint' definition, and worsening clinical and quality of life outcomes, across both MHA and SHA. Further analyses will seek to expand upon the initial results presented here, to investigate the wider elements of burden associated with compromised long-term joint health. Disclosures McLaughlin: BioMarin: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Roche/Chugai: Speakers Bureau; Takeda: Speakers Bureau. Hermans:Novo Nordisk: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; CAF-DCF: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; WFH: Other; EAHAD: Other; Octapharma: Consultancy, Speakers Bureau; Kedrion: Speakers Bureau; LFB: Consultancy, Speakers Bureau. Asghar:HCD Economics: Current Employment. Burke:HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Nissen:GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Dhillon:HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. . O'Hara:F. Hoffmann-La Roche Ltd: Consultancy; HCD Economics: Current Employment, Current equity holder in private company.

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An Insight into the Impact of Hemophilia a on Daily Life According to Disease Severity: A Preliminary Analysis of the CHESS II Study

Blood ◽

10.1182/blood-2020-136952 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-3

Author(s):

Declan Noone ◽

Francis Nissen ◽

Tao Xu ◽

Tom Burke ◽

Sohaib Asghar ◽

...

Keyword(s):

Board Of Directors ◽

Disease Severity ◽

Research Funding ◽

Hemophilia A ◽

Daily Life ◽

Social Activity ◽

Publicly Traded ◽

Advisory Committees ◽

On Demand ◽

The Impact

Introduction: Hemophilia A (HA) is a congenital bleeding disorder caused by a deficiency in clotting factor VIII (FVIII). There are currently limited data on the impact of HA on daily life. Here we examine the impact of HA on the daily life of adult persons with HA (PwHA) without current FVIII inhibitors according to disease severity. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey II (CHESS II) is a retrospective, burden-of-illness study in adults with mild, moderate, and severe HA or hemophilia B (defined by endogenous FVIII/IX [IU/dL] relative to normal; mild, 5-<40%; moderate, 1-5%; severe, <1%); this analysis includes only PwHA. Male participants (aged ≥18 years) diagnosed with HA (without FVIII inhibitors) at least 12 months prior to clinical consultation were enrolled from Denmark, France, Germany, Italy, the Netherlands, Romania, Spain, and the UK. Data on clinical outcomes and healthcare resource utilization were captured via electronic case report forms disseminated to hemophilia specialists. PwHA completed a paper-based questionnaire utilizing 5-point Likert scales to assess the disease burden on their daily life. Overall, 12 months' retrospective data were examined. Informed consent was obtained and the study was approved by the University of Chester ethical committee. Results: Of 258 PwHA completing questionnaires, 15.9% (n=41), 27.9% (n=72), and 56.2% (n=145) had mild, moderate, and severe HA, respectively. Of those with severe HA, 60.0% were currently receiving FVIII prophylaxis (standard of care for severe HA); in comparison, 4.9% and 6.9% of those with mild and moderate HA were receiving prophylaxis (Table 1). Treatment adaptation in anticipation of physical or social activity was reported by 19.5%, 23.6%, and 38.6% of those with mild, moderate, and severe HA, respectively. Over a third of participants with mild (36.6%) and moderate (44.4%) HA, and 64.8% of those with severe HA (58.6% with severe HA receiving on-demand treatment and 69.0% receiving prophylaxis) agreed or strongly agreed that HA had reduced their physical activity (Figure 1). Overall, 38.9% of those with moderate HA and 58.6% of those with severe HA (63.8% with severe HA receiving on-demand treatment and 55.2% receiving prophylaxis) agreed or strongly agreed that their HA had reduced their social activity; this was less pronounced in mild HA (9.8%). Additionally, 31.7%, 36.1%, and 64.1% of those with mild, moderate, and severe HA (62.1% with severe HA receiving on-demand treatment and 65.5% receiving prophylaxis) agreed or strongly agreed that their HA had caused them to miss opportunities. Correspondingly, frustration due to HA was felt by 19.5%, 34.7% and 57.9% (56.9% with severe HA receiving on-demand treatment and 58.6% receiving prophylaxis) of people, respectively. When asked whether they believed their daily life was compromised due to their hemophilia, 24.4%, 37.5%, and 63.4% of those with mild, moderate, and severe HA, respectively, agreed. Pain, as reported by the physician, was noted in 36.6% of people with mild HA (100% was reported as 'mild'); in people with moderate HA, pain was reported as 'mild', 'moderate', and 'severe' in 44.4%, 20.8%, and 1.4% of PwHA, respectively. In people with severe HA, pain was reported as 'mild', 'moderate', and 'severe' in 39.7%, 27.6%, and 8.6% for those receiving on-demand treatment, and 37.9%, 32.2%, and 8.0% for those receiving prophylaxis, respectively. Conclusions: In all disease severity groups, there was a notable group of PwHA that felt that they have had to reduce their physical and social activity, have had fewer opportunities and are frustrated due to their disease. While the impact on daily life is most pronounced in people with severe HA (including those receiving on-demand treatment and those receiving prophylaxis), it is also apparent in mild and moderate HA, indicating that there may be an unmet medical need in these groups. Disclosures Noone: Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; Research Investigator PROBE: Research Funding; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees. Nissen:F. Hoffmann-La Roche Ltd: Current Employment; Actelion: Consultancy; Novartis: Research Funding; GSK: Research Funding. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Burke:University of Chester: Current Employment; HCD Economics: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Asghar:HCD Economics: Current Employment. Dhillon:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; HCD Economics: Current Employment. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Khair:Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Haemnet: Membership on an entity's Board of Directors or advisory committees.

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

Blood ◽

10.1182/blood-2021-146143 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3185-3185

Author(s):

Robert F. Sidonio ◽

Alexis A. Thompson ◽

Flora Peyvandi ◽

Canan Albayrak ◽

Seoh Leng Yeoh ◽

...

Keyword(s):

Research Funding ◽

Hemophilia A ◽

High Titer ◽

Tolerance Induction ◽

High Dose ◽

Severe Hemophilia ◽

Publicly Traded ◽

Open Label ◽

Fviii Inhibitor ◽

Recombinant Fviii

Abstract Background The development of inhibitors to exogenous factor VIII (FVIII) is a serious treatment complication in patients with hemophilia A. Immune tolerance induction (ITI) is the only proven method for the eradication of FVIII inhibitors. This prospective, multicenter, open-label, phase 3 study (NCT02615691) is being conducted to determine the safety, immunogenicity, and efficacy of the extended half-life (EHL) recombinant FVIII rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in previously untreated patients (PUPs) with severe hemophilia A. The data presented here aims to evaluate the efficacy and safety of ITI therapy with rurioctocog alfa pegol in patients who developed FVIII inhibitors. Methods Eligible patients were ˂6 years of age with severe hemophilia A (FVIII <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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Real-World Efficacy of Venetoclax-Based Regimens in Patients with Chronic Lymphocytic Leukemia in Israel: A Multicenter Prospective Study

Blood ◽

10.1182/blood-2021-146504 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3727-3727

Author(s):

Yair Herishanu ◽

Neta Goldschmidt ◽

Gilad Itchaki ◽

Itai Levi ◽

Ariel Aviv ◽

...

Keyword(s):

Real World ◽

Interim Analysis ◽

Research Funding ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Publicly Traded ◽

Phase Iii Clinical Trials ◽

Medical Centers ◽

Grade 3

Abstract Background: The BCL-2 inhibitor venetoclax in combination with an anti-CD20 monoclonal antibody (rituximab or obinutuzumab) has demonstrated superior outcomes and manageable safety as compared to chemo-immunotherapy in phase III clinical trials for chronic lymphocytic leukemia (CLL). Moreover, venetoclax-based regimens induced high rates of undetectable minimal residual disease (uMRD). Prospective data on the effectiveness of venetoclax-based regimens specifically with regard to achieving uMRD in a real-world setting are still lacking. Here we report the first interim analysis for efficacy and safety of an ongoing nationwide real-world study of venetoclax based therapy for CLL/small lymphocytic lymphoma (SLL). Method: A prospective observational nationwide multicenter study. Treatment-naïve (TN) and relapsed/refractory (R/R) CLL/SLL patients were enrolled in 13 medical centers in Israel. The primary endpoint was clinical response, per physician assessment 12-months after the initiation of venetoclax treatment. Key secondary endpoints included progression free survival (PFS), overall survival (OS) and uMRD as assessed at a central laboratory by 8-color flow-cytometry. Results: Between February 10, 2019, and Jun 17, 2021 (data cut), 199 CLL/SLL patients were enrolled from 13 medical centers in Israel to receive venetoclax based therapy. The study included 83 TN and 116 R/R evaluable CLL/SLL patients with a median age of 69 years (range, 34-85) and 70.5 years (range, 25-91), respectively (Table 1). R/R patients had received a median of one prior therapy with a range up to 8, of these patients 60 (51.7%) were previously treated with a B-cell receptor inhibitor (BCRi) including ibrutinib in 52 (44.8%) and idelalisib in combination with rituximab in 6 (5.2%). TN patients had been treated with venetoclax in combination with obinutuzumab (92.8%) or rituximab (4.8%) and R/R patients received either venetoclax with rituximab (60.3%) or obinutuzumab (9.5%), venetoclax monotherapy (25.8%) or triple therapy with venetoclax, rituximab and ibrutinib in 5 (4.3%). Dose escalation of venetoclax to the recommended dose of 400 mg daily was achieved in 80.7% (n=67) of TN and 81% (n=94) of R/R patients. The median duration of ramp-up was 38 and 42 days in TN and R\R patients, respectively. Prior to therapy, tumor lysis syndrome (TLS) risk was considered high in 12% and 29.3% of TN and R/R patients, respectively (Table 1). Laboratory TLS occurred in one TN patient and 4 R/R patients, whereas 3 of the R/R patients experienced clinical TLS. Nineteen TN and 75 R/R patients had a follow-up of at least 12 months or discontinued study prematurely. The 12-month overall response rate (ORR) for TN and R/R patients was 89.5% [complete response (CR) 13 (68.4%), partial response (PR) 4 (21.1%)] and 73.3% [CR 37 (49.3%), PR 18 (24%)], respectively. In the R/R cohort, the 12-month ORR among assessed patients was 67.6% (25/37) in BCRi-exposed versus 85.7% (30/35) in BCRi-naïve patients. At 12 months, peripheral blood uMRD (<0.01%) was achieved in 12 out of 14 (85.7%) TN and 26 out of 38 (68.4%) R/R evaluated patients. At a median follow-up of 5.1 months (range, 0.5-15.6) for TN and 10.1 months (range, 0-25.7) for R/R patients, the median PFS and OS, for both cohorts have not been reached. The estimated 12-month PFS was 90.9% for TN and 81.1% for R/R patients. For R/R patients with prior exposure to BCRi, the estimated 12-month PFS was 69.6% versus 94.8% in BCRi-naïve patients (figure 1). Grade ≥3 adverse events (AEs) were reported in 34.9% of TN patients and 43.9% R/R patients. The most frequent grade ≥3 AEs documented were neutropenia (TN: 19.2% and R/R 17.2%), infections (TN: 4.8% and R/R: 21.5%) and febrile neutropenia (TN: 2.4% and in R/R: 2.6%). COVID-19 occurred in 7 patients including one death. At the time of data cut, 10 deaths occurred, one TN and 9 R/R patients. Causes for death included infections (5 patients), disease progression (2 patients), acute myeloid leukemia/ myelodysplastic syndrome (2 patients) and a soft-tissue sarcoma (1 patient). Conclusions: This first interim analysis of our ongoing prospective real-world study of venetoclax-based treatment for TN and R/R CLL/SLL, demonstrates high efficacy together with a high proportion of undetectable MRD levels and a favorable toxicity profile. These efficacy results are comparable to those reported in previous Phase III clinical trials for CLL, with no new safety signals. Figure 1 Figure 1. Disclosures Herishanu: AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; AstraZeneca: Honoraria. Goldschmidt: AbbVie: Consultancy, Research Funding. Itchaki: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Levi: AbbVie: Consultancy, Research Funding. Aviv: AbbVie: Honoraria, Research Funding. Fineman: AbbVie: Research Funding. Dally: AbbVie: Honoraria, Research Funding. Tadmor: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Ruchlemer: AbbVie: Consultancy, Honoraria, Research Funding. Abadi: AbbVie: Honoraria, Research Funding. Shvidel: AbbVie: Honoraria, Research Funding. Braester: AbbVie: Honoraria, Research Funding. Cohen: AbbVie: Current Employment, Current equity holder in publicly-traded company. Frankel: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ofek: AbbVie: Current Employment, Current equity holder in publicly-traded company. Berelovich: AbbVie: Current Employment, Current equity holder in publicly-traded company. Grunspan: AbbVie: Current Employment, Other: May hold equity. Benjamini: Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

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