scholarly journals Emicizumab in the treatment of hemophilia A

2020 ◽  
Vol 36 (81) ◽  
pp. 2007-2010
Author(s):  
Ivan Tijanić ◽  
Ivana Golubović ◽  
Miodrag Vučić ◽  
Miloš Tijanić
Keyword(s):  
Hemophilia A ◽  
Bleeding Events ◽  
Surgical Interventions ◽  
Hemostatic Activity ◽  
Adults And Children ◽  
Bleeding Episodes ◽  
Prophylactic Use ◽  
Bypassing Agents ◽  
Favorable Safety

Introduction: Despite substantial advances in the treatment of Hemophilia A with the use of concentrated factor VIII preparations during recent decades, bleeding episodes still occur from time to time. The development of inhibitors significantly reduces the efficacy of traditional replacement therapy, seriously increasing morbidity and mortality in these patients. Emicizumab (HEMLIBRA ®) is a chimeric bispecific humanized antibody that bridges activated FIX and FX and thus restores the function of missing activated FVIII. Aim: The aim of the study was to analyze the literature date of the effect of Emicizumab in the treatment of Hemophilia A. Results: Multicenter randomized studies called HAVEN have shown excellent results of this medication in the treatment of patients with Hemophilia A. FVIII inhibitors do not bind to or neutralize Emicizumab and therefore have no effect on the hemostatic activity of the drug. Emicizumab prophylaxis produced a significant reduction in treated bleedings of 79%, compared to with the group of patients on prophylaxis with bypassing agents, while the rate grew up to even 95% after longer observation. Other studies have also confirmed good treatment results and a favorable safety profile in both adults and children. In the cases of bleeding events or preparation for immediate surgical interventions, it is recommended to user FVII (NovoSeven) ® according to previous guidelines. Conclusion: The results of the prophylactic use of Emicizumabhave so far shown that it may be a revolutionary preparation that can significantly reduce bleeding episodes and improve the quality of life of patients with Hemophilia A. Nevertheless, further testing of this drug is required.

A Phase II Open-Label Study Evaluating Hemostatic Activity, Pharmacokinetics and Safety of Recombinant Porcine Factor VIII (OBI-1) in Hemophilia A Patients with Alloantibody Inhibitors Directed Against Human FVIII.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 783-783 ◽  
Author(s):  
Johnny Mahlangu ◽  
Tatiana A. Andreeva ◽  
Donald Macfarlane ◽  
Mark T. Reding ◽  
Christopher Walsh ◽  
...  
Keyword(s):  
Phase Ii ◽  
Hemophilia A ◽  
Dose Range ◽  
Vital Signs ◽  
Cross Reactivity ◽  
Bleeding Events ◽  
Open Label ◽  
Hemostatic Activity ◽  
Laboratory Variables ◽  
Bleeding Episodes

Abstract Development of inhibitors to human FVIII (hFVIII) is a significant complication in the reversal and prevention of bleeding events in hemophilia A patients. Porcine FVIII (pFVIII) possesses low cross reactivity to anti-hFVIII antibodies. OBI-1, a recombinant B-domain deleted pFVIII, has recently been tested in a Phase II trial in patients with congenital hemophilia A and inhibitors experiencing a non-life/non-limb threatening bleed. In patients with a measurable anti-pFVIII antibody titer, dosing was initiated with a loading dose (LD) followed by up to 8 doses of 50 to 150 U/kg of OBI-1 administered at 6 hour intervals until the bleed was controlled. The PK profile of OBI-1 was assessed for the first OBI-1 infusion of each patient. FVIII levels were measured 30 minutes after each infusion. Inhibitor titers were evaluated for a minimum of 6 months after the first OBI-1 infusion. A total of 25 bleeding episodes in 9 patients were treated successfully with OBI-1. The median time from bleeding onset to treatment was 7 hours (range: 3 20 hr). OBI-1 showed a cumulative efficacy of 72% after 1 injection, 84% after 2 injections or less, 92% after 3 injections or less, and 100% after 8 or less injections. In over 40 infusions, OBI-1 was well tolerated and no drug related SAEs were observed. One case of pruritus rated as mild was easily controlled with diphenhydramine. FVIII levels measured 30 minutes after each OBI-1 infusion ranged from < 0.5% to 226%. They were generally lower with higher anti-pFVIII titers although all bleeds were successfully controlled. Follow up inhibitor titers are still being monitored and final results will be presented and discussed. Other investigative parameters, including vital signs and laboratory variables did not show treatment related abnormalities. OBI-1 can be given as a short infusion. It was effective in controlling all bleeds which occurred in this study and was well tolerated. The results suggest that a LD is not needed with OBI-1 treatment, and in some instances patients may have been over treated. Given the promising results in this study, additional studies are planned to optimize dose range for OBI-1 and to confirm the long term safety and efficacy of OBI-1 in the treatment of bleeds in a larger cohort of individuals with hemophilia A complicated by the presence of hFVIII inhibitors.

scholarly journals Improvement of Efficacy Outcomes in Patients Who Switched from Sucrose-Formulated rFVIII to BAY 81-8973 Prophylaxis in the LEOPOLD Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Gili Kenet ◽  
Thomas Moulton ◽  
Erika Soltes Rak ◽  
Brian M. Wicklund ◽  
Sanjay P Ahuja
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Study Drug ◽  
Study Cohort ◽  
Efficacy And Safety ◽  
Old Patients ◽  
On Demand ◽  
Adults And Children ◽  
Previously Treated ◽  
Bleeding Episodes

Background BAY 81-8973 (Kovaltry®) is a full-length, unmodified, recombinant factor VIII (FVIII), indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding and routine prophylaxis to reduce the frequency of bleeding episodes in adults and children with hemophilia A. It has the same amino acid sequence as sucrose formulated FVIII (FVIII-FS; Kogenate® FS/Helixate® FS). Pharmacokinetic comparisons confirmed BAY 81-8973 to have a longer half-life and lower clearance than FVIII-FS. The objective of this analysis was to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS prior to enrolling into the LEOPOLD clinical studies receiving BAY 81-8973. Methods LEOPOLD I (NCT01029340) Part B and LEOPOLD Kids (NCT01311648) were Phase 3, multinational, open-label studies that included male patients with severe hemophilia A receiving on-demand or prophylactic therapy, with ≥50 exposure days to any FVIII product and no history of FVIII inhibitors. Patients in LEOPOLD I were &gt;12 years old and received 20-50 IU/kg BAY 81-8973 prophylaxis twice-weekly (2×W) or three times a week (3×W) for up to one year. Patients in LEOPOLD Kids were ≤12 years old and received 25-50 IU/kg BAY 81-8973 ≥2×W for six months. Dosing regimens for both studies were assigned by the investigator. In this analysis, efficacy and safety are assessed in the subset of patients in LEOPOLD I Part B and LEOPOLD Kids who were previously treated with FVIII-FS. Results In LEOPOLD I, 22 (35.5%) patients were previously treated with FVIII-FS with a median age of 27.0; in LEOPOLD Kids, 24 (47.1%) patients were previously treated with FVIII-FS with a median age of 5.0 (Table 1). In general, these switch cohorts had similar patient demographics to the whole study cohort (Table 1) and any differences did not affect the final analysis. Most patients did not change their dosing frequency when starting treatment with BAY 81-8973 but most increased their dose (FVIII-FS dose is 25 IU/kg 3×W [adults] or every other day [EOD; children]; BAY 81-8973 dose is 25-40 IU/kg 2×W or 3×W [&gt;12 years] or 25-50 IU/kg 2×W, 3×W or EOD [≤12 years]). Switching from FVIII-FS to BAY 81-8973 resulted in lower median annualized bleeding rates (ABRs) in the LEOPOLD studies. In LEOPOLD I, median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) in the 12 months of FVIII-FS treatment prior to study entry, to 1.0 (0.0; 6.8) (Figure 1). In LEOPOLD Kids, median total ABR decreased from 3.0 (1.0; 12.0) to 2.0 (0.0; 6.0) for 0-&lt;6 year old patients (n = 13) and from 4.0 (0.0; 10) to 0.0 (0.0; 2.1) for 6-12 year old patients (n = 11) after switching from FVIII-FS to BAY 81-8973 (Figure 1). Joint and spontaneous median ABRs were zero for &lt;12 year old patients treated with BAY 81-8973. There were no study-drug-related adverse events (AEs) or serious AEs (SAEs) reported in patients switching from FVIII-FS to BAY 81-8973 in either LEOPOLD I Part B or LEOPOLD Kids (Table 2). One patient in the LEOPOLD Kids main study discontinued BAY 81-8973 due to a central venous catheter-related infection after six months of treatment, which was not considered study-drug-related. No FVIII inhibitors developed in any patients in either study. Conclusions Switching from FVIII-FS to BAY 81-8973 resulted in improved bleeding control in adults and children with hemophilia A and was well-tolerated. Disclosures Kenet: PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Moulton:Bayer: Current Employment. Soltes Rak:Bayer: Other: Employee of Belcan, contracted with Bayer. Wicklund:Genentech: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Shire (Takeda): Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding.

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽  
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.

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3800-3800 ◽  
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.

Quality of life of adults and children with TRK fusion cancer treated with larotrectinib compared to the general population.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3614-3614
Author(s):  
Shivaani Kummar ◽  
Cornelis M. Van Tilburg ◽  
Catherine M. Albert ◽  
Jordan Berlin ◽  
Anna F. Farago ◽  
...  
Keyword(s):  
Quality Of Life ◽  
General Population ◽  
Normal Category ◽  
Eortc Qlq C30 ◽  
Adults And Children ◽  
Eortc Qlq ◽  
Favorable Safety ◽  
Tumor Types ◽  
Population Norm

3614 Background: NTRK gene fusions occur in diverse tumor types in adults and children. The selective TRK inhibitor, larotrectinib, has shown high response rates, durable disease control, and a favorable safety profile in patients (pts) with TRK fusion cancer. We report an expanded quality of life (QoL) analysis for pts treated with larotrectinib. Methods: QoL data were collected in two trials of larotrectinib in pts with TRK fusion cancer using EORTC QLQ-C30 (adults) and PedsQL (children) questionnaires, and were analyzed descriptively and longitudinally. EORTC QLQ-C30 global health scores (GHS) and PedsQL total scores range from 0 to 100, with higher scores indicating better QoL. We calculated the proportion of pts with normal/above and below normal QoL scores compared to values in the literature for the US general population. Results: By July 2019, 126 pts with TRK fusion cancer (74 adults, 24 children ≥2 yrs, and 28 infants <2 yrs) had received larotrectinib and completed baseline (BL) and ≥1 post-BL questionnaire. Most pts had clinically meaningful QoL improvements that reached or exceeded the minimally important difference (Table); a positive change from BL was also seen in infants: mean best change of 12.0 (SD 13.8). Of 52 adults with BL EORTC QLQ-C30 GHS at or above the population norm, 51 remained in this category on treatment and 1 moved into the below normal category. Of 22 adults with BL scores below the population norm, 20 moved into the normal/above normal category. All 9 children aged ≥2 yrs with BL PedsQL scores at or above the population norm remained in this category on treatment. Of 15 children with BL scores below the population norm, 10 moved into the normal/above normal category. Sustained QoL improvements (change from BL ≥0) occurred by 2 months of treatment in 69% of adults and 75% of children. Median duration of sustained improvement in EORTC QLQ-C30 GHS and PedsQL total score was 12.0 months (range 1.7–20.3) and not estimable (range 1.1–23.0), respectively. Conclusions: Adults and children with TRK fusion cancer treated with larotrectinib had rapid, clinically meaningful, and sustained improvements in QoL. Clinical trial information: NCT02576431, NCT02637687 . [Table: see text]

scholarly journals Thrombin Generation Assay in Plasma from Hemophilia a Patients with or without Inhibitors on Concizumab Prophylaxis: Spiking with rFVIIa or aPCC

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3639-3639
Author(s):  
Marianne Kjalke ◽  
Mads Kjelgaard-Hansen ◽  
Søren Andersen ◽  
Ida Hilden
Keyword(s):  
Thrombin Generation ◽  
Significant Contribution ◽  
Hemophilia A ◽  
Employment Equity ◽  
Breakthrough Bleeding ◽  
Thrombin Generation Assay ◽  
Bleeding Episodes ◽  
Equity Ownership ◽  
Bypassing Agents

Introduction: Concizumab is a humanized monoclonal antibody that inhibits tissue factor pathway inhibitor (TFPI). Concizumab is currently in clinical development as a subcutaneous prophylactic therapy for hemophilia A and B patients with and without inhibitors. Breakthrough bleeding episodes experienced by inhibitor patients while on concizumab prophylaxis may be treated with the bypassing agents recombinant activated factor VII (rFVIIa; NovoSeven®) or activated prothrombin complex concentrate (aPCC; FEIBA®). Aim: To investigate the in vitro effect of rFVIIa and aPCC on hemophilia A plasma containing concizumab using a thrombin generation assay and pooled plasma spiked with concizumab or samples from patients treated prophylactically with concizumab. Methods: Pooled hemophilia A plasma was spiked with concizumab at 1, 3 and 10 nM and patient plasma samples from explorer4 (n=16; hemophilia with inhibitors; NCT03196284) and explorer5 (n=30; hemophilia A; NCT03196297) before and during concizumab prophylaxis at steady state exposure levels were assessed. Samples were spiked with rFVIIa (25 or 75 nM) or aPCC (0.25, 0.5 or 1 U/mL), and analyzed using a thrombin generation assay initiated with tissue factor (PPP-Low, Thrombinoscope). The effects of rFVIIa or aPCC in the absence or presence of concizumab were compared using ANOVA methodology. Results: Addition of rFVIIa or aPCC to hemophilia A plasma with or without inhibitors increased peak thrombin generation both in the absence and presence of concizumab. A significant additional effect of rFVIIa and aPCC was observed for all concizumab concentrations spiked to the plasma pool. Overall, the effects of the combination of concizumab and rFVIIa or aPCC were mainly additive; however, a small but statistically significant drug-drug interaction was observed for rFVIIa (25 nM or 75 nM) and aPCC (0.5 U/ml or 1 U/mL) in the presence of 10 nM concizumab. At this concizumab concentration, the additive effect of aPCC corresponded to 68% of the total observed effect and the additive effect of rFVIIa to 85% of the total observed effect. At lower concizumab concentrations (1 and 3 nM), statistically significant drug-drug effects were only observed in combination with aPCC. No excessive thrombin generation above the level obtained with 1 IU/mL recombinant factor VIII (rFVIII) was observed at 1 nM concizumab combined with either rFVIIa (25 and 75 nM) or aPCC 0.5 U/mL. However, addition of 1 U/mL aPCC to 1 nM concizumab resulted in a thrombin peak modestly above the upper 95% confidence interval of the rFVIII range. In the experiments using plasma from patients treated with concizumab, the increase in thrombin peak upon addition of rFVIIa was within or below the range observed by spiking with 1 IU/mL rFVIII. The increase in thrombin peak upon addition of aPCC was within or above the rFVIII range. The effects of concizumab and rFVIIa or aPCC were mainly additive; however, a small, statistically significant contribution caused by drug-drug interaction was observed for concizumab and rFVIIa (75 nM) in both plasma from patients with and without inhibitors, and for 1 U/mL aPCC in plasma from patients with inhibitors. The additive effects of concizumab and rFVIIa corresponded to between 60% (25 nM rFVIIa, plasma without inhibitors) and 75% (75 nM rFVIIa, inhibitor plasma), and the additive effects of concizumab and 1 U/mL aPCC corresponded to 77% of the total observed effects. Conclusions: Addition of rFVIIa or aPCC to hemophilia A plasma with or without inhibitors increased peak thrombin generation as expected both in the absence and presence of concizumab. Thus, the bypassing agents function as expected in plasma containing concizumab. The effects of concizumab and rFVIIa or aPCC were mainly additive. A small but statistically significant contribution was synergistic in accordance with the concizumab mechanism of action (Hilden I et al, Blood, 2012). These in vitro results support the concomitant use of bypassing agents to treat breakthrough bleeding episodes in hemophilia with inhibitor patients on concizumab prophylactic treatment. Disclosures Kjalke: Novo Nordisk A/S: Employment, Honoraria. Kjelgaard-Hansen:Novo Nordisk A/S: Employment, Equity Ownership. Andersen:Novo Nordisk A/S: Employment, Equity Ownership, Honoraria. Hilden:Novo Nordisk A/S: Employment, Equity Ownership, Patents & Royalties.

scholarly journals Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry

Blood ◽  
2012 ◽  
Vol 120 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Francesco Baudo ◽  
Peter Collins ◽  
Angela Huth-Kühne ◽  
Hervé Lévesque ◽  
Pascual Marco ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Hemostatic Agent ◽  
Symptomatic Therapy ◽  
Bleeding Control ◽  
First Line ◽  
Acquired Hemophilia A ◽  
Acquired Hemophilia ◽  
Acquired Haemophilia ◽  
Bleeding Episodes ◽  
Bypassing Agents

AbstractAcquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

scholarly journals Immune Tolerance Induction Treatment Is Cost-Effective in Adult Patients with Long-Standing High-Responding Inhibitors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3530-3530
Author(s):  
Alessandra Nunes Loureiro Prezotti ◽  
Silmara Aparecida De Lima Montalvão ◽  
Cláudia Lorenzato ◽  
Andrea Maia Oliveira ◽  
Maria do Perpétuo Socorro Vendramini Orletti ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Tolerance Induction ◽  
Cost Effective ◽  
Adult Patients ◽  
Median Period ◽  
Long Time ◽  
Bleeding Episodes ◽  
The Mean ◽  
Bypassing Agents ◽  
Inhibitor Titer

Abstract Introduction: Despite treatment of hemophilia having achieved considerable improvement over the last decades, inhibitor development remains a major complication for these patients. Inhibitors are alloantibodies that neutralize factor (F) VIII coagulation activity, and occur in approximately 25% of hemophilia A patients. Immune tolerance induction (ITI) is the choice therapy to eradicate these antibodies. There are several ITI protocols with similar success rates, approximately 70%. The presence of long-standing inhibitors in the adult population has usually been associated with poor ITI outcome. In Brazil, as in other countries with constrained resources, limited access to factor concentrates prevented the use of ITI. Thus, almost all patients with inhibitors remained a long time with this complication. Only after 2013 with increased availability of factor concentrates in the country, has assured long-term prophylaxis and ITI treatment been possible. Objective: This study aimed to describe the Brazilian experience in managing ITI in adult patients from seven Hemophilia Treatment Centers with long-standing inhibitor using bypassing agents to control bleeding episodes, considering bleeding frequency, treatment barriers and economic impact of therapy. Patients and Methods: We retrospectively analyzed clinical and laboratory data of hemophilia A patients with high-responding inhibitors (peak titer > 5 Bethesda Unit (BU), anamnestic response to FVIII) over 18 yo who underwent ITI treatment and were using bypass agents before ITI. The initial ITI protocol used was low-dose FVIII concentrate (25-50 IU/kg 3x/week) Results: In Brazil, since the availability of ITI, 39 adult hemophilia A patients with inhibitors, have been submitted to ITI for the first time. In this study, we accessed data from 26 patients, of these 13 (50%) already achieved complete ITI success criteria (inhibitor titer < 0.6 BU; FVIII recovery ≥ 66%, and half-live ≥ 6 h). Another 4 patients with ongoing ITI achieved inhibitor titer < 5 BU and are no longer using bypassing agents. Thus, 17/26 (65%) patients discontinued the bypassing agents in a median period of 2 mo (range 0 to 18 mo) after starting ITI. After 24 months of irregular treatment 2 patients abandoned ITI protocol. Analyses of the 13 patients with complete success revealed mean age at first reported inhibitor of 16.21y (SD ± 11.6; median 21y, range 0.7 to 37y), and mean age at ITI onset of 31.2y (SD ± 10.6; median 27y, range 19 to 47y). The mean period from the first inhibitor detected until starting ITI was 15y (SD ± 5.1), with a 16y median (range 7 to 22y). The historical peak inhibitor mean was 53.1 BU (SD ± 49.5; median 39.4 BU, range 5.5 to 163 BU). The mean pre ITI inhibitor titer was 6.6 BU (SD ± 5.5; median 5.5 BU, range 0.6 to 20.8 BU). Low-dose ITI protocol was initially used for all patients, however 3 patients had the dose increased during treatment (100 IU/kg from 3 to 7 x/week). During ITI, 10/13 patients received prophylaxis with bypassing agents, and 9 began prophylaxis before ITI started. The mean time to achieve inhibitor titer < 0.6 BU was 11.6 mo (SD ± 12.5; median 7 mo, range 0.5 to 44 mo). All 13 patients achieved other ITI success criteria. However, a delay was observed in the majority of patients in FVIII recovery and half-life. Regarding clinical outcome, we observed a significant reduction in both, annualized bleeding rate (ABR), and annualized joint bleeding rate (AJBR), comparing 12 months before ITI, during ITI, and after achieving complete success (figure 1). Regarding economic evaluation, we observed a significant reduction in the median cost of clotting factor consumption, comparing 12 months before starting ITI, and the following years after achieving ITI success. No significant difference was observed between the median cost of 12 months before, and ITI period (figure 2). Conclusion: This study indicated that this treatment is worthwhile even for inhibitor patients with poor prognostic factors for ITI considering both effectiveness to control and prevent bleeding episodes, and economic impact. In this group, 65% of adult hemophilia A high-responding inhibitors patients stopped using bypassing agents after a median period of 2 months after starting ITI. Despite being a high cost treatment, ITI can be cost-effective, especially for patients using bypassing agents. These results reinforce the positive impact of the ITI even in long time inhibitor adult patients. Disclosures Ozelo: Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Biogen: Research Funding.

Long-Term Prophylaxis with Activated Recombinant FVII in Children with Hemophilia a and Inhibitor, Receiving Treatment with ITI Protocol

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4980-4980 ◽  
Author(s):  
Ekaterina Shiller ◽  
Victor Petrov ◽  
Pavel Svirin ◽  
Vladimir Vdovin ◽  
Igor Koltunov ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Factor Viii ◽  
Hemophilia A ◽  
Treatment Time ◽  
Conflicts Of Interest ◽  
Factor Vii ◽  
Treatment Level ◽  
Factor Viii Inhibitor ◽  
Bleeding Episodes

Abstract Background: Recent studies have shown that addition of bypassing agents to immuno-tolerance induction (ITI) protocol for patients with hemophilia A and inhibitor results in better control of bleeding episodes and improves quality of life. Few publications have addressed prophylactic usage of recombinant factors VIIa in these settings. Due to relatively low infusion volume, convenience of administration and high efficacy rFVIIa - Coagil-VII seems to be especially reasonable for ITI protocol. Aim: To assess the efficacy and safety of rFVIIa - Coagil-VII (SJC "GENERIUM", Russia) for prophylactic use during ITI protocol in patients with hemophilia A and inhibitor. Methods: Seven patients aged between 2 to 7 years with severe hemophilia A and inhibitor have been treated with ITI protocol using plasma derived factor VIII with von Willebrand factor. Seven of them simultaneously received treatment with Coagil-VII in individual doses (100-250 mkg/kg) and regimens (every 12 - 48 hours). When inhibitor reached level of 3 BU (Bethesda Unit) either dose or frequency of Coagil-VII administration were gradually reduced. After 1 BU the patients were given factor VIII only. Number and severity of bleeding events were assessed. Results: Five patients with high responding inhibitors and poor prognosis (history of high titer of factor VIII inhibitor, prolonged time between first inhibitor appearance and the beginning of ITI) received Coagil-VII in high doses 150 - 250 mkg/kg every 12-24 hours in 1-4 years. At time of booster effect titer of inhibitors reached 92 -16 000 BU. One of patients had ITI failure because of interruption of protocol, while 4 patients continue treatment. Level of 3 BU was reached by 4 patients at 40, 12, 35, and 3 months of treatment. Level of 1 BU was reached by 2 patients at 6 and 42 months of treatment. Significant clinical effect was achieved after 6 months of treatment. Time of bleeding episode was decreased from 7 (±2) to 2 (±1) days. Total number of hemorrhagic events, including hemarthrosis, hematomas and bleedings decreased by 3,7 fold (3,7 events per patient-month during first 6 months versus 1,0 events per patient-month). Only 1 hospital admission with bone fracture was recorded. All children have an active lifestyle and attend school. Two patients with low responding inhibitor and good prognosis received Coagil-VII in low doses 90 - 170 mkg/kg every 24-48 hours. Maximal titer of inhibitor was 1.3 - 1.9 BU. Both patients completed treatment with Coagil-VII in 2 and 4 months and continue ITI protocol and both achieved undetectable level of inhibitor. No bleeding episodes were recorded in these patients since the beginning of treatment. There was no clinical or laboratory evidence of thrombosis, thrombocytopenia, or disseminated intravascular coagulation. Conclusion: We report our experience of prolonged (2 months - 4 years) prophylactic treatment with recombinant activated factor VII (rFVIIa) - Coagil-VII in patients with hemophilia A and inhibitor. This prophylaxis is efficacious when doses and treatment regimens are individually determined. This approach results in reduction of bleeding episodes in all patients, as well as increase of quality of life. No any adverse events (AE and SAE) with prolonged use of Coagil-VII have been registered so far. Disclosures No relevant conflicts of interest to declare.

scholarly journals How I use bypassing therapy for prophylaxis in patients with hemophilia A and inhibitors

Blood ◽  
2015 ◽  
Vol 126 (2) ◽  
pp. 153-159 ◽  
Author(s):  
Cindy A. Leissinger ◽  
Tammuella Singleton ◽  
Rebecca Kruse-Jarres
Keyword(s):  
Physical Disability ◽  
Hemophilia A ◽  
Joint Disease ◽  
Clotting Factor ◽  
On Demand ◽  
Increased Risk ◽  
Related Quality ◽  
Health Related ◽  
Bleeding Episodes

Abstract Inhibitor development poses a significant challenge in the management of hemophilia because once an inhibitor is present, bleeding episodes can no longer be treated with standard clotting factor replacement therapy. Consequently, patients with inhibitors are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. Three clinical trials in patients with inhibitors have demonstrated that prophylaxis with a bypassing agent reduces joint and other types of bleeding and improves health-related quality of life compared with on-demand bypassing therapy. In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or FIX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined.

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