The Effects of Tranexamic Acid on Bleed Control, Coagulopathy and Survival with Trauma in Anemic Mice

Abstract Clinical evidence suggests that anemia increases surgical bleeding and is associated with poor outcomes. Globally, ~ 50% of anemia is attributed to iron deficiency as the most common nutritional disorder. To study the effects of iron deficiency anemia (IDA) on traumatic bleeding we developed a mouse model of IDA and traumatic injury, and tested the effects of prophylactic tranexamic acid (TXA), on blood loss, coagulopathy and survival. Materials and Methods C57BL/6J mice, both male and female, were fed with usual laboratory ("control mice") or iron deficient (4ppm iron) chow ("IDA mice") starting at 3 weeks of age. After 6 weeks, IDA was documented by blood count, red cell indices and liver iron content. Mice then were subjected to an established liver laceration model causing severe bleeding. Blood loss (weighing blood-soaked sponges in the abdominal cavity), seven-day survival and coagulation parameters (APTT, activity levels of Factor (F) V, FVIII, Fibrinogen) were determined at 15 and 60 minutes after liver laceration for "IDA" and "control mice", treated or not treated five minutes prior to injury with TXA (10mg/kg). All data were expressed as median and were compared using Mann-Whitney test. Results Compared to "control" mice, "IDA mice" developed hypochromic and microcytic anemia with a significantly lower mean hematocrit (32±1.7% vs 49±1.2%, p≤0.0001) and hepatic iron content (75.9±19.8µg/g vs 22.4±9.4 µg/g, p≤0.0001). "IDA mice" demonstrated significantly more bleeding after liver laceration compared to "control mice." Most of the bleeding had occurred at 15 minutes after injury with little incremental bleeding at 60 minutes. The blood loss in "IDA mice" was greater at both time points compared to "control mice" (15 minutes: 21.5±2.3µl/g vs 15.9±2.6µl/g, p≤0.0001; 60 minutes: 24.5±1.6µl/g vs 20.7±1.9µl/g, p≤0.0001). TXA reduced bleeding significantly in "IDA mice" at 15 and 60 min to ~15µl/g. In "control mice", bleed improvement was only present at 60 min (also reduced to ~15µl/g), without improvement below the ~15µl/g baseline threshold at 15 min. Coagulopathy developed in both groups over 60 min, with similar prolongation of the APTT from baseline (23.9±1.5s to 36.0±4.9s in "IDA mice"; 22.8±1.3s 35.0±3.8s in "control mice"), substantial depletion of FV and FVIII activity levels and partial reduction of fibrinogen. TXA administration normalized the APTT only in "control mice" at 60 minutes, but not in "IDA mice", although TXA reconstituted FV and fibrinogen to ~100% activity, with FVIII activity of ~50% in both groups. Survival of "IDA mice" was lower compared to "control mice" (50% vs 75%), but increased significantly with TXA (80%, p=0.04). Conclusion Enhanced bleeding and poorer survival was observed in "IDA mice" compared to "control mice" after liver laceration at similar degrees of coagulopathy. Prophylactic TXA corrected bleeding and reduced mortality in "IDA mice" to values similar to those observed for "control mice" despite incomplete correction of the coagulopathy in "IDA mice". This suggests that TXA may be of particular importance in the face of anemia, by mechanisms that may go beyond hemostasis correction alone, warranting further investigation. Disclosures von Drygalski: CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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GO-8: Preliminary Results of a Phase I/II Dose Escalation Trial of Gene Therapy for Haemophilia a Using a Novel Human Factor VIII Variant

Blood ◽

10.1182/blood-2018-99-118256 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 489-489 ◽

Cited By ~ 8

Author(s):

Amit C Nathwani ◽

Edward Tuddenham ◽

Pratima Chowdary ◽

Jenny McIntosh ◽

Doyoung Lee ◽

...

Keyword(s):

Gene Therapy ◽

Gene Transfer ◽

Phase I ◽

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Activity Levels ◽

Advisory Committees ◽

Preliminary Results ◽

Fviii Activity

Abstract Background: Haemophilia A (HA), the most common inherited bleeding disorder, is well suited for gene therapy because a modest increase in the plasma factor VIII (FVIII) levels to ≥1% of normal levels will substantially ameliorate the bleeding diathesis and improve quality of life. Earlier gene transfer strategies for FVIII replacement approaches using plasmid electroporation, retroviral vector, or adenoviral vector failed to achieve persistent phenotypic correction of bleeding. We have recently shown that a single peripheral vein administration of adeno-associated viral (AAV) vectors expressing the FIX transgene results in stable long-term expression of transgenic FIX at therapeutic levels without long term toxicity in patients with severe haemophilia B (ClinicalTrials.gov:NCT00979238). However, the use of AAV vectors for HA gene therapy has been limited by inefficient expression of transgenic FVIII and the large size of the FVIII cDNA. To overcome these obstacles, we developed two AAV-FVIII expression cassettes containing a small synthetic liver specific promoter (HLP) driving the expression of codon optimized FVIII variants. These vectors mediated therapeutic expression of FVIII in murine and non-human primate models (McIntosh et al 2013). The first of these constructs, AAV-HLP-hFVIII-SQ, encoding a B-domain deleted FVIII variant, was recently shown (Rangarajan et al, 2017) to mediate sustained (>1 year) normalisation of factor VIII activity in six of seven participants following a single intravenous infusion of AAV serotype 5 pseudotyped vector. However, high vector doses (6x1013 vector genomes/kg [vg/kg]) were required for efficacy, possibly because this product was manufactured using the insect cell/baculovirus system. In this report we describe the preliminary results of our on-going Phase I/II clinical trial (GO-8) evaluating the second FVIII cassette (AAV-HLP-hFVIII-V3), which contains a 17 amino-acid peptide comprising six N-linked glycosylation motifs from the human FVIII B-domain that are highly conserved through evolution. In murine studies, AAV-HLP-hFVIII-V3 mediated expression of FVIII at 3-fold higher levels when compared to AAV-HLP-hFVIII-SQ. Methods: The safety and efficacy of a single intravenous infusion of AAV8-HLP-hFVIII-V3, pseudotyped with AAV serotype 8 capsid was assessed in three adult men with severe hemophilia A (FVIII activity levels ≤1% of normal) in the context of an Investigator led, Phase I/II, open-label, non-randomized, dose-escalation trial (ClinicalTrials.gov: NCT03001830GO-8). The first subject received a dose of 6x1011vg/kg and the subsequent two patients each received a dose of 2x1012vg/kg. AAV8-HLP-hFVIII-V3 was manufactured in mammalian HEK 293T cells. The subjects have been followed up for 13-47 weeks after vector administration. Results: Peripheral vein administration of AAV8-HLP-hFVIII-V3 was well tolerated in all patients with no infusion-related reactions. Transgenic FVIII was detectable within two weeks and was more than 5 IU/dl by 6 weeks of gene transfer in all three subjects. Factor VIII activity (one stage clotting assay) levels have remained stable at 7±1IU/dl in patient 1 over a period of 47 weeks. The second participant is 20 weeks following administration of 2x1012 vg/kg of AAV8-HLP-hFVIII-V3 and has steady-state FVIII activity of 6±2IU/dl. In the third subject, who was also treated at a dose of 2x1012 vg/kg, the steady state FVIII activity is almost 10 times higher at 69±7 IU/dl. Elevation of serum alanine aminotransferase was observed in patients 1 and 3 at between weeks 4-6 after gene transfer, reaching peak levels that were 1.5 X upper limit of the normal range. Both patients were treated with corticosteroids within 48 hours of the onset of transaminitis with no loss of transgene expression. No participant has developed a FVIII inhibitor. Conclusion: Our preliminary results from the ongoing Phase I/II study demonstrate FVIII activity levels >5% in all three subjects with normalization of FVIII:C levels in one patient. These levels are sufficient to reduce/prevent spontaneous hemorrhage and have been achieved using relatively lower doses of AAV8-HLP-FVIII-V3 than reported previously with a related FVIII expression cassette. No Grade III (CTCAE v4.03) or greater adverse events have been observed over a period of 47 weeks after administration of AAV8-HLP-hFVIII-V3. Disclosures Nathwani: Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Tuddenham:Freeline: Consultancy; BioMarin: Consultancy, Patents & Royalties. Chowdary:Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta (Shire): Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum AB (Sobi): Honoraria; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Freeline: Consultancy. McIntosh:Freeline: Consultancy.

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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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Hypophosphatemia after High Dosage Iron Substitution with Ferric Carboxymaltose (FCM) and Iron Isomaltoside (IM) — the Randomised Controlled Home Afers 1 Trial

Blood ◽

10.1182/blood-2018-99-114386 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3627-3627 ◽

Cited By ~ 2

Author(s):

Insa E. Emrich ◽

Fabio Lizzi ◽

Seiler-Mußler Sarah ◽

Christian Ukena ◽

Dominic Kaddu-Mulindwa ◽

...

Keyword(s):

Iron Deficiency ◽

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Iron Deficiency Anaemia ◽

Ferric Carboxymaltose ◽

Advisory Committees ◽

Deficiency Anaemia ◽

Iron Substitution ◽

Plasma Phosphorus

Abstract In iron deficiency anaemia patients, intravenous administration of either ferric carboxymaltose (FCM) or iron isomaltoside (IM) both allow high dosage iron substitution within a single outpatient visit. In contrast, other iron compounds require repetitive, low dosage infusions. Recently, FCM was reported to frequently induce acute, reversible hypophosphatemia. It remains enigmatic whether these hypophosphataemic effects of FCM are substance-specific, or whether they generally occur after high dosage iron substitution. A direct comparison of phosphorus regulation after high dosage iron substitution with either FCM or IM is clinically important, as hypophosphatemia after FCM has anecdotally been associated with osteomalacia and bone fractures. In the HOMe AFers 1 (HOMburg evaluations on application of Ferrum study 1) trial, we recruited normophosphatemic women with gynaecological bleeding and subsequent iron deficiency anaemia, in whom we assessed the longitudinal biochemical response over 28 days to a single intravenous injection of equivalent doses of randomly-assigned FCM and IM (1000 mg). The primary study hypothesis was that the incidence of hypophosphatemia - defined as plasma phosphorus < 2.0 mg/dl at least out of three post-infusion study time points (day 1, day 8, and week 5) - differs between FCM and IM. HOMe AFers 1 initially planned to recruit 60 women. An interim analysis was pre-specified and scheduled in July 2018, with the option to stop further patient recruitment if the incidence of hypophosphatemia differs significantly at this interim analysis. At the time point of the interim analysis, 26 patients have been recruited. One patient withdrew her acceptance to participate after day 1, leaving 25 patients for our per protocol interim analysis. Baseline plasma phosphorus did not differ significantly between FMC (3.3 ± 0.4 mg/dl) and IM (3.6 ± 0.6 mg/dl; p = 0.135). Analysis on the primary endpoint demonstrated that significantly more women developed hypophosphatemia < 2.0 mg/dl after FMC infusion (9 out of 12 patients) than after IM infusion (1 out of 13 patient) (p=0.001). Further, the minimum plasma phosphorus during any of the three post-infusion study time points was lower after FMC (1.8 ± 0.3 mg/dl) than after IM (2.7 ± 0.6 mg/dl; p < 0.001). As expected, ferritin and haemoglobin increased in both study groups after iron infusion. No severe adverse events occurred in either group. In conclusion, while both FCM and IM provide efficient iron substitution in iron deficiency anaemia, FCM induced a substantially higher incidence of hypophosphatemia. Disclosures Emrich: Pharmacosmos: Consultancy, Honoraria, Research Funding. Stilgenbauer:Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Brandenburg:Pharmacosmos: Consultancy, Honoraria, Research Funding; Vifor: Consultancy, Honoraria. Heine:Pharmacosmos: Consultancy, Honoraria, Research Funding.

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A Survey of the Etiology of Immune Thrombocytopenia (ITP).

Blood ◽

10.1182/blood.v120.21.2239.2239 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2239-2239

Author(s):

Valerie Arias ◽

Ehsan Shabbir ◽

Daniel Victorio ◽

Emily Sperling ◽

Naznin Haq ◽

...

Keyword(s):

Statistical Analysis ◽

Family History ◽

Iron Deficiency ◽

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Deficiency Anemia ◽

Advisory Committees ◽

Formal Statistical Analysis ◽

History Of

Abstract Abstract 2239 Introduction: Socioeconomic, environmental, lifestyle and genetic factors play a role in the etiology of ITP but are poorly understood. A self-reported questionnaire was designed to study these relationships and how these factors prior to the diagnosis of ITP relate to treatment response and disease progression in order to gain insight into the etiology of ITP. Methods: To design the questionnaire that would address topics of interest: 1) 60 ITP patient interviews were performed and 2) the questionnaire was reviewed by project coordinators, nurse practitioners, Platelet Disorder Support Association (PDSA) members, and hematologists. The input was incorporated into a further-revised questionnaire, which was then administered to both “pediatric” (patients <18 years of age at the time of diagnosis) and adult ITP patients from the Platelet Disorders Center at Weill Cornell - New York Presbyterian Hospital. Formal statistical analysis to relate responses to one question to responses of another to define sub-groups of patients is ongoing. Results: 109 patients were enrolled. Ages ranged from 2–78 years of age; median age was 55 years, with 21 females and 33 “pediatric” patients. The most frequent environmental exposures in adults were automotive exhaust (n=14) and Teflon (n=12). In pediatrics, preservatives and insecticides (n=8) and Teflon (n=7) were most common. The most prevalent hazardous substances in both groups were cleaning supplies (n=16 adults, n=9 “pediatric”) and chlorinated water (n=13 adult, n=9 “pediatric”). 13 adults also had exposure to gasoline or diesel fumes. Refer to figure 1. 51(47%) patients reported at least one infection prior to diagnosis with ITP. The most common were Strep throat (n=12); influenza (n=9), and respiratory tract infections (n=8). Twenty-four (22%) patients reported at least one autoimmune disease, including celiac (n=2) and discoid lupus (n=2).Twenty-one patients reported a family history of Type II diabetes, 12 Type I diabetes, 13 osteoarthritis and 10 rheumatoid arthritis. Eight (7%) patients reported at least one inflammatory disease including: Crohn's disease (n=3), Inflammatory bowel disease (n=7), Systemic lupus erythematous and Vitiligo(each n=1). Thirty-seven (34%) patients reported surgeries prior to diagnosis of ITP, especially: appendectomy (n=8) and tonsil removal (n=8). Twenty-three patients traveled close to date of diagnosis, 58 patients reported more stress than usual (i.e. death of a relative, loss of employment); 13 patients reported a drastic change in diet (i.e. decreasing calories (n=7) or becoming vegetarian (n=5)). Vitamin supplementation for vitamin C and D (each n=17), E (n=12) and B (n=11) were common. In addition, 11 vitamin deficiencies were reported, vitamin D (n=5), vitamin B12 (n=3) and other (n=3). The most frequent allergic reactions included: 31 (28%) patients with hay fever, 9 patients with allergies to milk, 7 patients with poison ivy or skin irritation, 6 patients with eczema, and 4 with allergic rhinitis. Other medical conditions reported were: hypothyroidism (n=10), hyperthyroidism (n=9), high blood pressure (N=16), high cholesterol (N=14), and anemia (N=13) [9 additional patients included 4 with iron deficiency anemia and 5 with a family history of iron deficiency anemia]. Seven patients reported a lack of prenatal care in their mothers' pregnancy and 7 were premature. Medications reported include: acetaminophen (n=53), antibiotics (n=36), antihistamines (n=22), and hormone therapy (n=17). Vaccinations received close to date of diagnosis include: flu vaccine (n=10) and T-dap (n=9). Prednisone was reported most frequently as both the best therapy to minimize symptoms (n=18) and the worst (n=16). Conclusion: Our pilot study intended to capture critical information and to further development of the questionnaire. We can see if there are groups of patients in whom onset and other characteristics relate to outcomes including response to treatment. Following formal statistical analysis of the material acquired (in progress and anticipated by early September), the next step will be for a final updated version of the questionnaire to be posted on the PDSA web site in order to accrue responses from a much larger number of patients. The questionnaire will also be given to a non-ITP patient population to serve as controls. Disclosures: Bussel: Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

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Predicting FIX Activity in Prophylaxis Patients Using Recombinant FIX Fc Fusion Protein for Treatment of Bleeding Episodes

Blood ◽

10.1182/blood.v124.21.2842.2842 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2842-2842

Author(s):

Jerry S Powell ◽

Margareth Ozelo ◽

Margaret V. Ragni ◽

John Pasi ◽

David J. Perry ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Activity Levels ◽

Factor Activity ◽

Median Dose ◽

Employment Equity ◽

Advisory Committees ◽

Educational Support ◽

Bleeding Episodes ◽

Equity Ownership

Abstract Introduction: Prophylaxis with replacement factor IX (FIX) therapies can reduce the frequency of bleeding episodes in patients with severe hemophilia B. There is currently a lack of data on factor activity levels in patients that treat bleeding episodes while adhering to a prophylactic regimen. The phase 3 B-LONG study (Powell et al. NEJM 2013) demonstrated that recombinant factor IX Fc fusion protein (rFIXFc) had a prolonged half-life relative to recombinant FIX, and that rFIXFc was efficacious and safe for prophylaxis and treatment of bleeding in subjects with hemophilia B; previous reports have evaluated treatment of bleeding in all subjects in B-LONG, including those receiving episodic treatment with rFIXFc. The purpose of this analysis was to assess the efficacy of rFIXFc for the treatment of bleeding in patients that received rFIXFc prophylaxis in the B-LONG study. Additionally, FIX activity levels were predicted under scenarios where treatment of bleeding occurred in close proximity to prophylactic doses using a population pharmacokinetic (PK) modeling approach. Methods: B-LONG included previously treated male subjects ≥12 years of age that had moderately-severe to severe hemophilia B (≤2 IU/dL endogenous FIX activity). Treatment of bleeding was assessed in subjects receiving weekly prophylaxis (Arm 1) and individualized interval prophylaxis (Arm 2). The number of bleeds, median dose per infusion to treat a bleed, and number of infusions to resolve bleeds were evaluated. Predicted activity levels were generated for 1000 hypothetical patients using a three-compartment population PK model that was developed using PK data from B-LONG (n=123) and a phase 1/2a study of rFIXFc (n=12). Factor activity was predicted assuming that bleeds were treated with 50 IU/kg rFIXFc either 24 hours before or 24 hours after a scheduled prophylactic dose for patients on regimens of 50 IU/kg weekly (at steady-state). The treatment of bleeding dose was selected because it was in the recommended range in the B-LONG study and was consistent with the median dose per infusion used in B-LONG. The 50 IU/kg weekly regimen was the most common starting prophylactic regimen in B-LONG; 24 hours was selected to approximate the shortest time interval between separate treatment of bleeding and prophylactic doses. Results: In Arm 1 of B-LONG, bleeding episodes were reported in 47 of 61 subjects, and there were 167 episodes in total. In Arm 2, 67 episodes were reported in 15 of 26 subjects. The median annualized bleeding rate (ABR) was 2.95 in Arm 1 (median spontaneous ABR 1.04) and 1.38 in Arm 2 (median spontaneous ABR 0.88). In Arm 1, 85% of bleeding episodes resolved with 1 infusion and the median dose per infusion was 47.11 IU/kg (interquartile range [IQR] 31.75-56.03). In Arm 2, 85.1% of bleeding episodes resolved with 1 infusion and the median dose per infusion was 44.78 IU/kg (IQR 33.63-74.33). rFIXFc was generally well-tolerated, and there were no vascular thrombotic events reported in any arm of the B-LONG study. The predicted median Cmax from the population PK model was in the normal range for both scenarios (Table 1; Figure 1). Figure 1A: FIX activity over time for hypothetical patients that treat a bleeding episode while on prophylactic regimens. Graphs correspond to scenarios as labelled in Table 1. Figure 1A:. FIX activity over time for hypothetical patients that treat a bleeding episode while on prophylactic regimens. Graphs correspond to scenarios as labelled in Table 1. Figure 1B Figure 1B. Conclusions: Predictions of factor activity from a population PK model showed that the vast majority of patients maintained factor activity within the normal range when rFIXFc was dosed in close proximity for both prophylaxis and to treat a bleeding episode. These predictions also indicated that maximum plasma concentration was achieved rapidly. An analysis of bleeding episodes in subjects specifically from the prophylaxis arms of B-LONG showed that rFIXFc was a safe and efficacious treatment for bleeding in patients on prophylactic regimens. Disclosures Powell: Bayer: Research Funding; Baxter Healthcare: Research Funding; Biogen Idec: Research Funding; CSL Behring: Research Funding; Novo Nordisk: Research Funding. Ozelo:Bayer: Research Funding; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk Haemophilia Foundation: Research Funding. Ragni:Pfizer: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Merck: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Tacere Benitec: Consultancy, Drug Safety Monitoring Board, Drug Safety Monitoring Board Other; GlaxoSmithKline: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Biogen Idec: Consultancy, Research Funding; Spark Therapeutics: Research Funding; Vascular Medicine Institute, PIttsburgh, PA: Research Funding. Pasi:Bayer: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Educational Support and Travel Grants, Educational Support and Travel Grants Other, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Educational Support and Travel Grants, Educational Support and Travel Grants Other; OctaPharma: Educational Support and Travel Grants Other, Membership on an entity's Board of Directors or advisory committees; Pfizer: Educational Support and Travel Grants Other, Membership on an entity's Board of Directors or advisory committees. Perry:Biogen Idec: Consultancy, Research Funding; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Baxter: Honoraria. Zhu:Biogen Idec: Employment, Equity Ownership. Mei:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Li:Biogen Idec: Employment, Equity Ownership. Robinson:Biogen Idec: Employment, Equity Ownership.

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A Phase 3 Study of the Hepcidin Mimetic Rusfertide (PTG-300) in Patients with Polycythemia Vera

Blood ◽

10.1182/blood-2021-149219 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1504-1504

Author(s):

Srdan Verstovsek ◽

Andrew T. Kuykendall ◽

Ronald Hoffman ◽

Yelena Ginzburg ◽

Naveen Pemmaraju ◽

...

Keyword(s):

Iron Deficiency ◽

Polycythemia Vera ◽

Board Of Directors ◽

Research Funding ◽

Data Safety Monitoring Board ◽

Publicly Traded ◽

Phase 3 ◽

Eligibility Criteria ◽

Advisory Committees ◽

To Receive

Abstract Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) alone or in combination with either hydroxyurea (HU), ruxolitinib (RUX) or interferon (IFN) to maintain hematocrit (HCT) levels below 45% as per NCCN guidelines. Since patients are seen periodically, PV patients may spend significant time with HCT levels above 45%, thereby increasing their risk of thrombosis [Marchioli NEJM 2013]. PV is associated with systemic symptoms with fatigue. These fatigue-related symptoms are found to be the most prevalent and severe as reported in an international survey among PV patients [Scherber Cancer 2016]. Symptomatic iron deficiency represents an unaddressed clinical challenge to PV patients as most PV patients have iron deficiency at diagnosis due to increased iron utilization [Ginzburg Leukemia 2018]. The iron deficiency worsens after repeated TP. We have demonstrated in a phase 2 study that rusfertide (PTG-300) has a good tolerability profile and achieves HCT control in PV patients with improvement in iron deficiency. Methods. This is a Phase 3, multicenter, global, randomized trial that compares the efficacy and safety of rusfertide compared to placebo when added on to current therapy for PV (Figure 1). The study population is PV subjects who require frequent phlebotomies to control their hematocrit with or without concurrent therapy. This is a three-part study in subjects with polycythemia vera: - Part 1a: randomized, double-blind, placebo-controlled, add-on parallel-group period for 32 weeks. Subjects will be stratified by their ongoing PV treatment and randomized 1:1 to rusfertide or placebo added-on to their ongoing PV treatment. - Part 1b: open-label treatment phase during which all subjects who complete Part 1a successfully will receive rusfertide for 20 weeks (Week 32 through Week 52). - Part 2: Long term extension (LTE) phase during which all subjects who complete Part 1b will continue to receive rusfertide for 32 weeks (Week 52 to Week 84). Inclusion Criteria: Approximately 250 subjects will be randomized. Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and frequent phlebotomies with or without concurrent cytoreductive therapy to maintain HCT below 45% in the 6 months prior to enrollment in Part 1. Eligible subjects will continue to receive their therapy at screening for PV (phlebotomy alone (TP) or cytoreductive therapy + TP) and must have a hematocrit <45% at Week 0 prior to randomization. Subjects who meet the eligibility criteria will be stratified by ongoing PV therapy (TP only, TP+hydroxyurea, TP+ruxolitinib, TP+interferon, TP+other) and randomized 1:1 to treatment with rusfertide or placebo added on to the subject's ongoing PV therapy at Week 0. The "add on" design allows subjects to receive standard cytoreductive therapy to control WBC and/or platelets and to receive rusfertide/placebo. The dose of cytoreductive therapy in Part 1a and Part 1b may be decreased for safety but may not be increased for efficacy including control of hematocrit, elevated platelets and/or WBC. Primary endpoint: Proportion of subjects achieving a response starting at Week 20 through Week 32 (inclusive) who receive rusfertide compared to placebo. A response is defined as absence of phlebotomy eligibility defined as either: 1. a confirmed hematocrit ≥45% and that is at least 3% higher than the baseline hematocrit (value immediately prior to randomization at Week 0); confirmation required within 1 to 7 days, or 2. a hematocrit ≥48%. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Kuykendall: Pharmaessentia: Honoraria; Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria; Abbvie: Honoraria; Incyte: Consultancy; Blueprint: Honoraria. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding. Pemmaraju: Incyte: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; Sager Strong Foundation: Other; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. O'Connor: Protagonist Therapeutics: Current Employment. Gupta: Protagonist Therapeutics: Current Employment. Kiladjian: Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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Iron Deficiency Anemia in Infants and Toddlers – Role of Milk and Constipation

Blood ◽

10.1182/blood.v120.21.5171.5171 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5171-5171

Author(s):

Madhavi Lakkaraja ◽

Lesley Small ◽

Maura Frank ◽

Aliza Solomon ◽

Nicole Kucine ◽

...

Keyword(s):

Iron Deficiency ◽

Board Of Directors ◽

Research Funding ◽

Deficiency Anemia ◽

Infants And Toddlers ◽

Iron Intake ◽

Advisory Committees ◽

Phone Calls ◽

History Of ◽

Equity Ownership

Abstract Abstract 5171 Introduction: One of the most common nutritional deficiencies in the world is iron-deficiency anemia and young children are at high risk of developing it. In spite of fortification of foods in the United States, there is a high prevalence of anemia in infants and toddlers increasing their risk of neuro-developmental effects. Constipation is defined as delay or difficulty in defecation ≥ 2 weeks. Around one year of age, various changes are commonly implemented in a child's diet including introduction of whole milk and solids. Children may then present with sub-clinical colitis, constipation and anemia secondary to blood loss in stool or develop anemia due to increased consumption of milk. The American Academy of Pediatrics (AAP) recommends screening for anemia at 1 year and 2 year visits. The only clue to intolerance to milk may be symptomatic constipation and treating the anemia and switching the type of milk often helps to resolve this problem. This study explores the relation between iron deficiency, constipation and milk. Methods: This is an ongoing prospective study, which has been extended from Cornell to different centers. Data presented here is only from the Cornell principal site. Children between 6 months and 30 months visiting the resident's pediatric clinic and having routine blood work drawn as a part of their visit were included in the study. The National Health Sciences (NHS) Constipation questionnaire was administered to the parents of these children; ≥ 2 was considered Constipation. In addition, a detailed diet history of the child, and history of medicines and illness was taken and questions were asked about family history of anemia, constipation and allergies. If the mother was breast feeding, questions were asked about her dairy intake. Comparisons were made between children with and without constipation/iron deficiency. If the child had Hemoglobin (Hgb) <11, the child was started on Iron as per clinic policy, and phone calls were made to check for compliance with Iron. In addition letters including a printed calendar and a note on Iron rich foods were mailed out to the parents. Results: Two hundred five children, 92 females and 113 males between 8 and 30 months mean age 16. 7 months, are enrolled in the study. Seventy-two children (35 %) were constipated (score ≥2). Forty-two children (20. 5%) had Hgb <11. Children who had Hgb < 11 were not more constipated (45%) than those who had Hgb ≥11 (35%). In the Hgb <11 group, there was no significant difference in Hgb between children with and without constipation (p = 0. 19), however there was a difference in Hgb between infants with a Constipation score 0 and score 1 (p = 0. 03). Of the 42 children who had Hgb <11, 3 were later found to have sickle trait or alpha thalassemia trait, which were identified when iron intake did not improve the Hgb level. Compliance with Iron: Of the 39 children who were on Iron, 9 parents could not be reached via phone. Only 6 parents gave no Iron at all but another 12 did not give Iron properly resulting in 18/30 or 60% of infants/toddlers not receiving an adequate trial of replacement Iron. Among the side effects of Iron, one parent felt Iron caused rash on back and wanted multivitamin with Iron after finishing a month's course, one child had discoloration of teeth, so the parent gave it with juice. Two parents with infants with apparent true milk protein allergy colitis said constipation improved with diet change and iron. Conclusions: The prevalence of mild anemia is high in infants and toddlers. There was no clear association of constipation and anemia. Compliance is one of the key factors for Iron replacement therapy and in view of how erratic compliance was, it is imperative to give proper instructions to the parent while prescribing Iron. Material to better indicate which foods were rich in iron and follow-up phone calls were included in the management to optimize iron intake of anemic children. We will include more patients, more closely monitor the change in the diet of the child, and monitor responses to Iron therapy in children with low Hgb. In addition, different practices at other involved centers e. g. Brooklyn hospital Center may allow comparison of the time of screening (9 months v/s 1 year) and testing with Hemoglobin/Hematocrit versus a full Complete Blood Count with indices. Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shinogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Portola: Consultancy.

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Association Of Bleeding Tendency With Time Under Target FIX Activity Levels In Severe Hemophilia B Patients Treated With Recombinant Factor IX Fc Fusion Protein

Blood ◽

10.1182/blood.v122.21.2349.2349 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2349-2349 ◽

Cited By ~ 5

Author(s):

Amy Shapiro ◽

James Potts ◽

Shuanglian Li ◽

Leonard A. Valentino ◽

Lei Diao ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia B ◽

Activity Levels ◽

Bleeding Tendency ◽

Severe Hemophilia ◽

Bleeding Events ◽

Advisory Committees ◽

Episodic Treatment ◽

Equity Ownership

Abstract Introduction The goal of prophylactic treatment with coagulation factor replacement in hemophilia patients has been to convert severe hemophilia, defined as <1% endogenous factor activity levels, to moderate (1% to 5%) and mild (5 to 40%) disease. It has been reported that increased time spent under 1% FVIII activity was associated with an increase in total bleeding episodes and hemarthroses in patients with severe hemophilia A (Collins PW, J Thromb Haemost 2009). Since no studies to date have documented this association for FIX activity in patients with severe hemophilia B, we examined the bleeding tendency in relation to FIX activity using data from the B-LONG study. The B-LONG study evaluated the pharmacokinetics (PK), safety, and efficacy of a recombinant FIX Fc fusion protein (rFIXFc) in severe hemophilia B patients (Powell J, J Thromb Haemost 2013). Briefly, the B-LONG study had 4 treatment arms: weekly prophylaxis, tailored prophylaxis, episodic treatment, and perioperative management. The corresponding median annualized bleeding rates for the first 3 treatment arms were 2.95, 1.38, and 17.69, respectively. Methods A 3-compartmental population PK model of rFIXFc was developed based on activity-time profiles in 12 subjects from a Phase 1/2a study and 123 subjects (>12 years) from B-LONG, collected over ≤ 52 weeks of treatment (Diao L, EAHAD 2013). Individual post-hoc PK parameters were then derived to construct continuous FIX activity-time profiles for each dose administered over the course of the study for all subjects in B-LONG. The cumulative time under target 1%, 3%, and 5% FIX level for each individual on study was calculated and normalized to obtain annualized time under the respective target FIX level. Negative binomial regression models were used to evaluate associations between the number of bleeding events (overall, spontaneous, traumatic, and joint) and annualized time (days) under 1%, 3%, and 5% of FIX activity for all subjects in B-LONG. Models were adjusted for age, body mass index, baseline HIV and HCV status, FIX genotype, number of bleeding episodes in the 12 months prior to study entry, and each subject's time on study. Results The multivariable negative binomial regression analysis estimated that overall bleeding events increased with increased time spent under 1% of FIX activity (p<0.001). The association, however, is largely driven by subjects on episodic treatment. The median annualized time under 1% for subjects on episodic treatment was 171 days, in contrast to the median of 0 days for subjects on either weekly prophylaxis or tailored prophylaxis, respectively, as the tailored PK-driven dosing regimens were designed to maintain a target trough above 1%. The association is consistent with the distribution of bleeding events, most of which occurred at predicted FIX activity levels under 1% in subjects on episodic treatment. Since the distribution of predicted FIX trough levels in subjects on prophylaxis were largely in the range of 1% to 5%, the analysis was repeated for cumulative time under 3% and 5%. Both analyses found statistically significant increases in predicted bleeding events as time spent below the respective FIX activity levels increased (Figure 1). The significant association was also observed for spontaneous, traumatic, or joint bleeds analyzed separately for all 3 target FIX activity levels. When comparing across thresholds (1% vs. 3% vs. 5%), the predicted bleeding rate was significantly reduced and the predicted probability of being bleed-free improved as the trough increased. Additionally, the odds of having joint bleeds increased significantly with increasing time spent under the respective target trough (1%, 3%, or 5%). Conclusions This is the first study to demonstrate a correlation between increased time spent under a target therapeutic FIX activity level (1%, 3% or 5%) and increased bleeding tendency, as well as a reduced probability of being bleed-free in patients treated with rFIXFc, suggesting that rFIXFc can provide protection from bleeding in a manner similar to endogenous FIX. These findings also confirm the importance of a minimum therapeutic threshold of 1% and provide additional support for establishing effective rFIXFc prophylaxis using population PK simulation. Disclosures: Shapiro: Baxter: Consultancy, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Global steering committees, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Inspiration: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; Biogen Idec: Research Funding. Potts:Biogen Idec: Employment. Li:Biogen Idec: Employment. Valentino:Baxter Healthcare: Consultancy; Bayer: Consultancy; Biogen Idec: Consultancy; GTC Biotherapeutics: Consultancy; Inspiration Biopharmaceuticals: Consultancy; Novo Nordisk: Consultancy. Diao:Biogen Idec: Employment, Equity Ownership. Wang:Biogen Idec: Employment. Robinson:Biogen Idec: Employment. Pierce:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership.

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The Bleeding Tendency In Relation To Predicted FVIII Activity Levels In Severe Hemophilia A Patients Treated With Recombinant Factor VIII Fc Fusion Protein

Blood ◽

10.1182/blood.v122.21.3590.3590 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3590-3590 ◽

Cited By ~ 1

Author(s):

John Pasi ◽

James Potts ◽

Shuanglian Li ◽

Ping Wang ◽

Sarah Kulke ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Negative Binomial ◽

Hemophilia A ◽

Bleeding Tendency ◽

Severe Hemophilia ◽

Advisory Committees ◽

Episodic Treatment ◽

Fviii Activity ◽

Bleeding Episodes

Abstract Introduction Prophylactic regimens with coagulation factor in patients with hemophilia A have been designed to maintain FVIII activity above 1 IU/dL, based on previous studies demonstrating that joints can be preserved and bleeding is minimized when circulating factor levels remain above this level (Nilsson IM, et al. J Intern Med 1992). Collins and colleagues confirmed this observation and demonstrated that increasing time spent under 1 IU/dL FVIII activity in patients on prophylaxis with recombinant FVIII (rFVIII) was associated with an increase in bleeding episodes and hemarthroses (Collins PW, et al. J Thromb Haemost 2009). The pharmacokinetics (PK), safety, and efficacy of rFVIII Fc fusion protein (rFVIIIFc) have been evaluated in the A-LONG study and recently reported (Mahlangu J, et al. J Thromb Haemost 2013). Briefly, previously treated male patients, ≥12 years old with severe hemophilia A, were enrolled in A-LONG and allocated to 1 of 3 treatment arms: Arm 1) individualized prophylaxis with dose and dosing interval adjustments (25–65 IU/kg every 3–5 days) based on PK and clinical indications, Arm 2, fixed dose (65 IU/kg) weekly prophylaxis, and Arm 3, episodic treatment (10–50 IU/kg) for bleeding episodes. The median annualized bleeding rates for individualized prophylaxis and weekly prophylaxis were 1.6 and 3.6, respectively, and 33.6 for episodic treatment. In this analysis, we evaluated the bleeding tendency in relation to predicted FVIII activity levels in 163 subjects in the A-LONG study. Methods A 2-compartment population PK model of rFVIIIFc was developed based on activity-time profiles in 180 severe hemophilia A subjects aged 12 – 65 years old (16 from a Phase 1/2a study and 164 from A-LONG collected over ≤ 52 weeks of treatment) (Neelakantan S, et al. J Thromb Haemost 2013). Individual post-hoc PK parameters were derived to construct continuous FVIII activity-time profiles for each dose administered over the course of the study for 163 subjects in A-LONG. The cumulative time under 1IU/dL FVIII levels for each individual on study was calculated and normalized to obtain annualized time under 1IU/dL. Negative binomial regression models were used to evaluate associations between the number of bleeding episodes (overall, spontaneous, traumatic, and joint) and annualized time (days) under 1IU/dL FVIII activity. Models were adjusted for age, body mass index, baseline HIV and HCV status, baseline von Willebrand factor, number of bleeding episodes in the 12 months prior to study entry, and each subject’s time on study. Results The predicted median annualized time under 1IU/dL FVIII activity for subjects on episodic treatment was 224.81 days, which was shortened to 51.55 days in subjects on a fixed prophylactic dose of 65 IU/kg of rFVIIIFc once weekly, and further reduced to 2.17 days in subjects on tailored prophylactic regimens (25 – 65 IU/kg, every 3 – 5 days). Multivariable negative binomial regression analysis showed that the number of overall bleeding episodes increased with increased time spent under 1IU/dL of FVIII activity level (p<0.001). A significant association was also observed for the time under 1IU/dL and the individual bleed types (spontaneous, traumatic, and joint) when analyzed separately. In addition, across all subtypes of bleeding, there was a significant decrease in the odds of being bleed-free for each one day increase in the time spent under 1IU/dL of FVIII activity. Conclusions In subjects treated with rFVIIIFc in the A-LONG study, there was a significant association between increased time spent under 1IU/dL of FVIII activity and increased bleeding tendency, as well as decreased odds of being bleed-free. The findings reinforce the importance of a therapeutic threshold of 1 IU/dL of FVIII activity as reported previously, and contribute to building a stronger foundation for designing effective rFVIIIFc prophylactic dosing regimens based on population PK simulations of FVIII activity. Disclosures: Pasi: Bayer: Membership on an entity’s Board of Directors or advisory committees; Bio Products Laboratory Ltd: Membership on an entity’s Board of Directors or advisory committees; OctaPharma : Membership on an entity’s Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding. Potts:Biogen Idec: Employment. Li:Biogen Idec: Employment. Wang:Biogen Idec: Employment. Kulke:Biogen Idec: Employment. Pierce:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership.

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Blocking Protein S Improves Hemostasis in Hemophilia a and B

Blood ◽

10.1182/blood.v128.22.79.79 ◽

2016 ◽

Vol 128 (22) ◽

pp. 79-79

Author(s):

Luca Bologna ◽

Raja Prince ◽

Mirko Manetti ◽

Daniela Melchiorre ◽

Irene Rosa ◽

...

Keyword(s):

Blood Loss ◽

Board Of Directors ◽

Tissue Factor ◽

Research Funding ◽

Hemophilia A ◽

Protein S ◽

Advisory Committees ◽

Intense Staining ◽

Preliminary Results

Abstract Introduction&Aim Hemophilia A and B are X-linked disorders caused by an absence or a reduction in coagulation FVIII and respectively, FIX. Patients with hemophilia often suffer from spontaneous bleeding within the musculoskeletal system, such as hemarthrosis. Here, we investigated whether targeting protein S (PS) could promote hemostasis in hemophilia by re-balancing coagulation. PS is a natural anticoagulant, acting as non-enzymatic cofactor for activated protein C (APC) in the inactivation of FVa and FVIIIa, and for tissue factor pathway inhibitor (TFPI) in the inhibition of FXa. This dual role makes PS a key regulator of the inhibition of thrombin generation (TG). Methods & Results Hemophilic (F8-/- or F9-/-) Pros1+/- mice were intercrossed. F8-/-Pros1-/- and F9-/- Pros1-/- mice were viable and found at the expected Mendelian frequency with no increased mortality compared to hemophilic mice. F8-/-Pros1-/- mice did not show DIC onset neither an increased mortality once challenge with tissue factor (TF). Ex vivo evaluation of TG potential showed that F8-/-Pros1-/- mice were APC-resistant, they had an improved low TF induced-TG and a 20% more dense fibrin network with larger fibrin fibers diameter as compared to F8-/-mice. Comparable results were found in human HA plasma where blocking PS raised TG even in the presence of high inhibitor titer. To assess the in vivo effect of PS inhibition on HA mice hemostasis, two tail- clipping (TC) assays were used. In both, mild TC model (2 mm cut) and severe TC (4 mm cut), blood loss significantly decreased in F8-/-Pros1-/- compared to F8- /- mice (mild TC: 407±21 vs 661±29ul, p<0.0001; severe TC:173±14 vs 249±24ul, p<0.05). In addition, the infusion of anti-hPS antibody on F8-/-Pros1+/- mice, reduced the blood loss compared to F8-/-Pros1+/- mice infused with an isotype IgG (196±10 vs 302±25ul, p=0.005). As recurrent joint bleeding is the most common manifestation of HA, we challenged F8-/-Pros1-/- mice in an acute hemarthrosis (AH) model. Joint swelling 72 hours after injury was reduced in F8-/-Pros1-/- compared to F8-/- (0.11±0.03 vs 1.02±0.07mm, p<0.0001, n=10). These results were also confirmed by s.c. injection of anti-hPS antibody (0.46±0.0 vs 0.78±0.09mm isotype IgG, p=0.02, n=9) and by i.v. injection of PS-siRNA prior to AH challenge in F8-/-Pros1+/- (0.29±0.09 vs 0.92±0.12mm siRNA control, p=0.03, n=5) and F8-/- mice(0.35±0.08 vs 0.78±0.09mm siRNA control, p=0.05, n=5). Similar results were obtained in F9-/-Pros1-/- mice. Histological analysis of joint showed joint bleeding reduction in F8-/-Pros1-/- compared to F8-/- and an increased fibrin staining comparable to F8+/+ mice.To understand the intra-articular hemostatic effect of blocking PS, joint sections were stained for TFPI. Preliminary results indicate a massive staining in the synovia of F8-/- mice, while F8-/-Pros1-/- and F8+/+ mice present a less intense signal. These data suggest that the intra-articular space is a modulable anticoagulant environment. Human HA joint tissues were then analyzed for both PS and TFPI. A strong signal was found for TFPI and PS in the synovial lining and sublining layers of HA patients on demand (n=7). Interestingly, PS and TFPI stainings were remarkably decreased in HA patients under prophylaxis (n=5). Joint section from osteoarthritis patients (n=7) did not show an intense staining for TFPI and PS similarly to hemophilic patients under prophylaxis. To understand the improved phenotype of F8-/-Pros1-/- after AH, the function of macrophages were investigated. At the steady state, F8-/-Pros1-/- presented significantly 2-fold increased levels of inflammatory macrophages (M1) than in F8-/- mice. In addition bone marrow derived macrophages from F8-/-Pros1-/- exhibit 10-fold higher RBC phagocytic activity than F8-/- . Preliminary results indicate an increase of a monocyte attractant MCP-1 level, in knee lavage after AH in F8-/-Pros1-/- than F8-/- mice. Conclusion These data provide the first evidence that blocking PS has the ability to ameliorate hemophilia as judged by in vivo improvement of bleeding phenotype in the TC assay as well as in the AH model, suggesting a new valuable tool for hemophilia therapy. In addition, the modulable presence of PS and TFPI in human and mice joints is a novel pathophysiological aspect of hemarthrosis and constitutes a potential therapeutical target. Disclosures Kremer Hovinga: NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL-Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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