Natural History Of Hemophilic Joint Disease Using Sensitive Imaging With Magnetic Resonance Imaging (MRI)

Abstract Introduction Arthropathy, the most costly chronic complication of severe hemophilia A (HemA) can be prevented by routine replacement of factor VIII (FVIII) when initiated prior to joint bleeding (primary prophylaxis) [NEJM;357:535]. However, the efficacy of prophylaxis initiated after the onset of recurrent hemarthroses or with established arthropathy (secondary or tertiary prophylaxis) is unknown. This individual patient meta-analysis was performed to derive the natural history of arthropathy in HemA patients treated only in response to acute bleeding (on demand therapy) as a baseline for future work to estimate the amelioration of arthropathy attributable to secondary or tertiary prophylaxis. Methods Data from individual participants in 3 studies who received on demand therapy were aggregated into a single database. Eligibility for this analysis included FVIII ≤ 2%, negative history for inhibitor, bleeding history for 12 months prior to study data acquisition and assessment of both ankles, knees and elbows; joints were assessed using physical examination (PE) and T2* gradient echo MRI scored as previously described using the World Federation of Hemophilia Gilbert score and the 45 point extended MRI scales [Haemophilia;6:649; ISTH OP Mon 7/1/13, 9 am]. MRI data were divided into soft tissue and osteochondral changes. Bleeding and Gilbert data for all 6 joints and MRI data for knees and ankles were analyzed using standard descriptive statistics and regression methods to quantify the rate of change in scores of joint damage with age. Results The 3 studies included the Joint Outcome Study [NEJM;357:535] and the JOS Continuation Study (JOSc), the Spinart Study baseline results [JTH;11:1119] and a Cross-Sectional MRI study [Haemophilia;189 Suppl3:117]. The 3 studies provide data on 275 individuals aged 1 to 50 years. Clinical, Gilbert and MRI data were extracted and analyzed from multiple joints in each of 157 individuals who were receiving on-demand treatment only. The median age was 21 (range 1 – 50), and across all studies the median number of bleeding episodes in the prior 12 months was 18 (range 0 to 82). The rate of change in outcomes as a function of age is shown in Table 1 and Figure 1. The number of bleeding episodes was approximately constant at 20 bleeding episodes per year regardless of age (Figure 1a; p = 0.72 for relationship with age). Gilbert scores showed a steeper rise in young patients but did not increase after the late teens (Figure 1b; change of 0.34 Gilbert points/year of life, p=0.07). MRI scores, in contrast to bleeding rates and Gilbert scores, showed continued age-related deterioration (Figure 1c; change of 2 MRI points/year of life, p < 0.0001). Age-related total and osteochondral deterioration on MRI increased steadily with age (on average 2 MRI-points/year of age, p < 0.0001 for each), whereas soft tissue scores increased rapidly to approximately 9 by age 20, and then plateaued at a score of approximately 10 for ages 20-50 (0.08 MRI points/year, p =0.28). Conclusions Individual patient meta-analysis of bleeding frequency, joint PE and MRI joint structure was useful to determine the natural history of hemophilic arthropathy in patients treated with on-demand therapy, and showed a continuous increase in joint bone and cartilage abnormalities across the age span despite an early leveling in bleeding rate and joint physical function. These data will be critical to determine the quantitative effects of prophylaxis on mitigation of joint deterioration when initiated at various ages following the onset of joint bleeding. Disclosures: Manco-Johnson: Bayer HealthCare: Research Funding. Lundin:Bayer HealthCare: Research Funding. Hong:Bayer HealthCare: Employment. Oldenburg:Octapharma AG: Consultancy, Investigator Other. Manco-Johnson:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; NovoNordisk: Membership on an entity’s Board of Directors or advisory committees; Eisai: Research Funding.

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A Global Registry of Patients with Paroxysmal Nocturnal Hemoglobinuria.

Blood ◽

10.1182/blood.v114.22.3007.3007 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3007-3007

Author(s):

Robert Brodsky ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Monica Bessler ◽

Jeffrey Szer ◽

...

Keyword(s):

Bone Marrow ◽

Natural History ◽

Board Of Directors ◽

Research Funding ◽

Health Care Services ◽

Clinical Symptoms ◽

Marrow Transplant ◽

Advisory Committees ◽

Care Services ◽

History Of

Abstract Abstract 3007 Poster Board II-983 Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis which can lead to life-threatening complications including thrombosis, kidney disease, and pulmonary hypertension. The natural history of PNH is highly variable and has previously been captured by retrospective assessment. However, the clinical presentation and prognosis of the disease has changed with the increased awareness of PNH, the increased use of more sensitive diagnostic tests, and the availability of new treatment. Specifically, the development of targeted but potentially life-long therapies, such as terminal complement blockade, necessitates the collection of long-term outcomes data in this patient population. We have established a global PNH Registry in order to redefine the natural history of PNH capturing a wide range of patients from all over the world. The goal of the present analysis is to describe the data collected for the patients in the Registry and demonstrate its use as an ongoing repository of information on symptoms, course, complications and treatment in patients with a PNH clone. The first patient was enrolled in January 2005, with data contributed from 62 clinical sites in 12 countries on 4 continents as of July 2009. Patients are included in the Registry regardless of amount of clone, bone marrow pathology, symptoms, or treatments. Sites collect data at enrollment and every 6 months including demographics, diagnostics and flow cytometry, other lab tests including LDH, medical conditions such as bone marrow pathology and major adverse vascular events (MAVE), clinical symptoms, medications and transfusions, qualitative assessments, bone marrow transplant, and mortality. Patients complete a questionnaire every 6 months including health-related quality-of-life, symptoms, and use of health care services. As of July 2009 there were 368 enrolled patients in the Registry (51% female, 49% male). Mean age at enrollment was 43.6 ±16.7, while mean age at first PNH symptoms was 35.9±16.7. At enrollment, median GPI-deficient granulocyte percentage (GPI-DG) was 80.4%, while 10% of patients had a GPI-DG <10. Of those patients with a GPI-DG <10, 81% had bone marrow pathology (62% with aplastic anemia, 16% with myelodysplastic syndrome, 3% other pathology) compared to 38% of patients with GPI-DG 350. MAVE was increased in patients with GPI-DG 350 compared to <10 (22% vs. 8%), as were LDH levels (median 1042 vs. 239 U/L). Patients with GPI-DG <10 reported high levels of significant clinical symptoms (fatigue 59%; dyspnea 52%; abdominal pain 41%) and symptom reporting was generally increased in patients with higher GPI-DG levels. Treatment in the year prior to Registry enrollment primarily consisted of transfusions (42%), anticoagulation therapy (30%), eculizumab (29%), and immunosuppression (23%), although these varied by GPI-DG level. Clinicians assessed 14% of patients with a Karnofsky score of 70 or lower (i.e., not capable of work or normal activity). Patients' assessment of their overall health, social functioning, and fatigue worsened and use of health care services increased with higher GPI-DG. At this time, median follow up is 12.8 months, although 25% of patients have been followed for at least 30 months. Two patients received a bone marrow transplant and 8 are deceased. In conclusion, preliminary data show that greater GPI-DG is associated with less underlying bone marrow pathology, more hemolysis, more thromboses, and more patient-reported symptoms. New clinical sites and geographic regions are encouraged to participate in the Registry ([email protected]). This global PNH Registry should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Brodsky: Alexion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Muus:Alexion: Membership on an entity's Board of Directors or advisory committees. Bessler:Alexion: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees. Rotoli:Author Deceased: Author Deceased. Maciejewski:Celgene: Speakers Bureau; Gemzyne: Research Funding; Taligen: Membership on an entity's Board of Directors or advisory committees. Socie:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua:Alexion: Membership on an entity's Board of Directors or advisory committees. Rosse:Alexion: Membership on an entity's Board of Directors or advisory committees. Karnell:Alexion: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Characteristics of Patients without Bleeding in a Pivotal Trial of Extended Half-Life, Pegylated, Full-length Recombinant Factor VIII (BAX 855) in the Treatment of Hemophilia A

Blood ◽

10.1182/blood.v126.23.1105.1105 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1105-1105

Author(s):

Alice D. Ma ◽

Robert Klamroth ◽

Marilyn J. Manco-Johnson ◽

Werner Engl ◽

Jacqueline A Dyck-Jones ◽

...

Keyword(s):

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Prophylactic Treatment ◽

Employment Equity ◽

Advisory Committees ◽

On Demand ◽

Bleeding Episodes ◽

Equity Ownership ◽

The One

Abstract BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on ADVATE (rFVIII) with an extended half-life and is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. In the pivotal trial, previously treated patients (PTPs) received BAX 855 prophylaxis with a twice-weekly 45 IU/kg dosing regimen. Of 101 patients in the per protocol analysis set, 40 (39.6%) patients achieved zero bleeding during 6 months of prophylactic treatment with BAX 855, compared with the on-demand treatment arm in which every patient (n=17) experienced at least 1 bleeding episode. Pharmacokinetic parameters were assessed in a subset of patients with zero bleeding (n=9). Assessments were performed for rFVIII, for an initial infusion of BAX 855 and for a repeat infusion of BAX 855 after 6 months of treatment. Using the one-stage clotting assay, BAX 855 demonstrated an extended circulation time compared to rFVIII with a mean (standard deviation [SD]) half-life (T1/2) of 16.13 (3.827) hours vs 11.44 (2.250) hours (ratio BAX 855/rFVIII: 1.4). Over time, the 6 month assessment of BAX 855 T1/2 remained stable at 16.30 (3.137) hours (ratio repeat/initial BAX 855: 1.0), based on the one-stage clotting assay. Incremental recovery (IR) measurements were comparable with 2.41 (0.454) IU/dL for rFVIII and 2.62 (0.684) IU/dL for BAX 855. As expected, clearance (CL) was higher for rFVIII compared to BAX 855: 0.0380 (0.009) vs 0.0205 (0.007) dL/(kg*h). Historical annualized bleeding rates (ABRs) in the 40 patients without bleeding during prophylactic treatment were calculated based on the previous 3-6 months of each patient's diary or recall. Historical ABRs ranged from 0-80 with a median ABR of 7. However, patients may have either been receiving on demand or prophylactic FVIII treatment prior to entering the prophylactic arm of the trial, accounting for the range in ABRs. The median pre-trial ABR of patients in the on-demand arm, all of whom experienced bleeding, was much higher at 41.5 (range: 12.9-67.9). Of the 40 patients without bleeding who were in the prophylaxis arm of the trial, 31 received prophylaxis in their previous pre-trial regimen, while 9 had received on-demand treatment prior to enrolling in the trial. A target joint was defined as a single joint (ankles, knee, hip, or elbow) with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period. At screening, 30% of patients without bleeding on the study had 0 target joints, while 37.5% had 1-2 and 32.5% had ≥3 target joints. Of the patients who had >3 target joints at screening, there were 4 (10%) patients with 4 and 1 (2.5%) patient with 6 target joints at screening. In contrast, patients in the on-demand group (who had all been treated on-demand prior to the trial) had a higher incidence of target joints at screening: 11.8% of patients had 0 target joints, while 52.9% had 1-2 and 28.3% had ≥3 target joints. The presence or absence of preexisting arthropathy did not seem to influence the likelihood of having zero bleeding during the trial. In 65% of the patients without bleeding, arthropathy was present at screening. This is higher than was found in the patients treated on-demand (47.1%) who all experienced bleeding. A patient was considered to have arthropathy if it was indicated in the medical history or if the patient had joint surgery. Blood group types were collected on the patients without bleeding. The results showed: A-50%; B-12.5%; AB-7.5%; O-15%; unknown 15%. This is rather different than the blood types of the 17 on demand patients who all experienced joint bleeding: A-35.3%; B-5.9%; AB-17.6%; O-35.3%; unknown 5.9%. There were fewer blood group O patients among the patients without bleeding. While some of the characteristics of patients on prophylaxis without bleeding episodes were similar to those of patients treated on-demand who all experienced bleeding, patients without bleeding had fewer target joints at screening, lower median historical ABR, and lower incidence of blood type O. Disclosures Ma: Kedrion: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: 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; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Klamroth:Biogen and SOBI: Honoraria, Speakers Bureau; Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau. Manco-Johnson:Baxter/Baxalta, Bayer, CSL Behring, Biogen NovoNordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding. Engl:Baxalta: Employment, Equity Ownership. Dyck-Jones:Baxalta: Employment. Abbuehl:Baxalta: Employment, Equity Ownership.

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Safety and Longer-Term Efficacy of Concizumab Prophylaxis in Patients with Hemophilia a or b with Inhibitors: Results from the Extension Part of the Phase 2 explorer4 Trial

Blood ◽

10.1182/blood-2020-139910 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 40-41

Author(s):

Amy D Shapiro ◽

Giancarlo Castaman ◽

Katarina Cepo ◽

Sidsel Marie Tønder ◽

Tadashi Matsushita ◽

...

Keyword(s):

Board Of Directors ◽

Dose Level ◽

Research Funding ◽

Main Part ◽

Prophylactic Treatment ◽

Phase 2 ◽

Advisory Committees ◽

On Demand ◽

Term Efficacy ◽

Bleeding Episodes

Introduction Concizumab is a high-affinity, anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody currently in clinical investigation for the once-daily subcutaneous prophylactic treatment of patients with hemophilia. We present results from the combined main and extension parts (at least 76 weeks) of the phase 2 explorer4 trial (NCT03196284), which aimed to assess the safety and longer-term efficacy of concizumab in patients with hemophilia A with inhibitors (HAwI) and hemophilia B with inhibitors (HBwI). Methods explorer4 comprised a main part, which lasted at least 24 weeks for all patients, and an extension part, which lasted at least 52 weeks. The primary objective of the main part of explorer4 was to assess the efficacy of concizumab in preventing bleeds in patients with HAwI/HBwI, evaluated as annualized bleeding rate (ABR) at the last dose level after at least 24 weeks. This objective has been addressed in previous reporting of the main part of the trial (Shapiro A, et al. Blood 2019; 134[22]:1973-1982). During the main part of the trial, patients were randomized 2:1 to receive either concizumab prophylaxis or on-demand treatment with recombinant activated factor VII (rFVIIa). At the end of the main part, patients in the rFVIIa on-demand arm were switched to 0.15 mg/kg concizumab for the extension part. Concizumab dose was escalated to 0.20 and 0.25 mg/kg in both the main and extension parts if a patient experienced ≥3 treated spontaneous bleeding episodes within 12 weeks and if deemed safe by the investigator. The objective of the extension part of the trial was to assess safety and longer-term efficacy of concizumab. Endpoints included ABR after at least 76 weeks of treatment, concizumab and free TFPI concentrations prior to last dose administration at 76 weeks, number of adverse events (AEs) and occurrence of anti-drug antibodies (ADAs) during 76 weeks of treatment. ABR was estimated using LS-means estimates, based on a negative binomial regression with log of exposure time to concizumab in main and extension part as offset. Results Twenty-five patients with inhibitors were exposed to concizumab during the explorer4 trial; 15 with HAwI and 10 with HBwI. Eight of these patients received on-demand treatment with rFVIIa during the main part of the trial before receiving their first concizumab dose in the extension phase. The estimated ABR at the last dose level for all patients treated with concizumab during the main and extension parts was 4.8 (95% CI: 3.2-7.2), while during the trial this was 5.7 (95% CI: 4.2−7.8) (Table 1). During the main and extension parts, 4 (16%) patients had zero treated bleeding episodes on their last dose level. Plasma concentrations of concizumab were variable during the extension part of the trial (Table 2). Increased concizumab concentration was observed in patients who received concizumab 0.20 mg/kg; these patients also had lower concentrations of free TFPI (Table 2). There were no AEs leading to withdrawal, no thromboembolic events and no deaths during the main and extension parts of the trial. ADAs developed in 6 patients. Elevated prothrombin fragment 1+2 and D-dimer levels were observed in some patients treated with concizumab. Conclusions Results from the combined main and extension parts of the phase 2 explorer4 trial were in line with the clinical proof of concept established in the main part of the trial and provided further details of the safety and longer-term efficacy of subcutaneous prophylactic treatment with concizumab for at least 76 weeks in patients with HAwI and HBwI. Disclosures Shapiro: BioMarin: Research Funding; Agios: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; OPKO: Research Funding; Daiichi Sankyo: Research Funding; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Glover Blood Therapeutics: Research Funding; Octapharma: Research Funding; Pfizer: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding. Castaman:Uniqure: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ablynx: Honoraria; Alexion: Honoraria; Bayer: Honoraria; Baxalta/Shire: Honoraria; Sobi: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Werfen: Speakers Bureau; Kedrion: Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Cepo:Novo Nordisk: Current Employment. Marie Tønder:Novo Nordisk: Current Employment. Matsushita:Sysmex: Honoraria; Octapharm: Honoraria; Bayer: Consultancy, Honoraria; Novo Nordisk: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Shire/Takeda: Honoraria; Bioverative/Sanofi: Honoraria; CSL: Honoraria; JB: Honoraria; KMB: Honoraria; Kirin: Honoraria; Nichiyaku: Honoraria. Young:Bayer, CSL Behring, Freeline, UniQure: Consultancy; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria; Genentech/Roche, Grifols, and Takeda: Research Funding. Zupancic-Šalek:NovoNordisk Health Care AG: Honoraria, Speakers Bureau; Baxter: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Octapharma: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sobi: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau. Jimenez Yuste:NovoNordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Honoraria; Sobi: Consultancy, Honoraria, Research Funding; CSL: Honoraria; Octapharma: Honoraria.

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On-Demand Treatment of Bleeding Episodes in Patients with Hereditary Factor X Deficiency Using a High-Purity Factor X Concentrate: Data from 2 Clinical Trials and a Data-Collection Study

Blood ◽

10.1182/blood-2018-99-111397 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1215-1215

Author(s):

James N. Huang ◽

Chioma Akanezi ◽

Amy Shapiro

Keyword(s):

Data Collection ◽

Board Of Directors ◽

Research Funding ◽

Perioperative Management ◽

Factor X ◽

Open Label ◽

Phase 3 ◽

Advisory Committees ◽

On Demand ◽

Bleeding Episodes

Abstract Introduction: Hereditary factor X (FX) deficiency is a rare bleeding disorder characterized by spontaneous joint, mucosal, and muscle bleeds as well as intracranial hemorrhage. Women and girls may also experience menorrhagia. In the past, hereditary FX deficiency has been treated with fresh frozen plasma or a prothrombin complex concentrate, both of which contain variable amounts of FX. Plasma-derived FX (pdFX) is a high-purity FX concentrate approved in the United States for on-demand treatment of patients with hereditary FX deficiency aged 12 years and older and for perioperative management of bleeding in patients with mild hereditary FX deficiency. pdFX is approved in the European Union for treatment and prophylaxis of bleeding episodes as well as perioperative management in patients with hereditary FX deficiency. Objectives: To present efficacy and safety data from 2 phase 3 clinical studies and 1 data-collection study evaluating pdFX for on-demand treatment of bleeds in patients with hereditary FX deficiency. Methods: Results from 2 phase 3 clinical studies and 1 data-collection study of patients with severe (FX activity [FX:C] <1 IU/dL) or moderate (FX:C 1-5 IU/dL) FX deficiency are included. TEN01 was a prospective, open-label, multicenter, nonrandomized study of subjects aged ≥12 years. Bleeds were treated with an initial dose of 25 IU/kg pdFX followed by additional doses as needed. TEN02 was a prospective, open-label, multicenter, nonrandomized study in children less than 12 years old. In TEN01 and TEN02, pdFX efficacy was assessed as excellent, good, poor, or unassessable. TEN05 was a retrospective, multicenter data-collection study in patients of any age who received ≥1 dose of pdFX on a compassionate-use basis. Investigators retrospectively rated pdFX treatment of bleeds as effective (with hemostasis achieved with the expected number of doses for the severity of the bleed), not effective, or unknown. In TEN05, dosing was at the discretion of the investigator. All protocols were approved by each center's local or national independent ethics committee. All subjects provided written informed consent prior to enrollment. Results: A total of 19 subjects were analyzed from the 2 prospective clinical trials; 12 of these subjects were also included in the retrospective data-collection study. Ages ranged from 1 to 58; 16 of 19 patients were aged ≥12 years. FX deficiency was severe in 17 patients and moderate in 2 patients. During the studies, 326 bleeds were reported, with a median of 12 (range 1-59) bleeds per patient in TEN01, 4 (1-5) bleeds per patient in TEN02, and 5.5 (2-26) bleeds per patient in TEN05. Of these 326 bleeds, 270 bleeds in 18 subjects were treated with pdFX and evaluated. Severity was major for 108 bleeds, minor for 116 bleeds, and not rated for 46 bleeds. Reported bleed causes were menorrhagia (n=97), spontaneous (n=93), trauma or injury (n=75), other (n=3), and unknown (n=2). Bleed locations were mucosal (n=117), joint (n=79), muscle (n=38), other (n=30), and unknown (n=6). Most bleeds (n=230, 85.5%) were treated with a single pdFX infusion (the maximum number of infusions for a single bleed was 12). The total factor dose per bleed per subject ranged from 7.92 to 82.0 IU/kg, with a median of 25.0 IU/kg in TEN01, 31.7 IU/kg in TEN02, and 23.8 IU/kg in TEN05. Treatment effectiveness was assessed by investigators as excellent or good in 43 of 44 rated bleeds (97.7%) in TEN01 and TEN02. One was rated poor in TEN01. In TEN05 pdFX was reported as effective in all 79 rated bleeds (100%). In TEN01, 6 adverse events in 2 patients were reported as related or possibly related to pdFX treatment; all were mild or moderate. No adverse events in TEN02 were considered related or possibly related to pdFX treatment, and no adverse drug reactions or safety concerns were reported in TEN05. No thromboembolic events, inhibitor development, or hypersensitivity reactions were reported in the 3 studies. Conclusions: Across 3 studies, pdFX was rated as effective at treating a variety of bleeds in patients with FX deficiency. Only one dose of pdFX was needed to treat most (85.5%) bleeds. At the doses used in these studies, on-demand pdFX treatment was well tolerated in pediatric and adult subjects. Disclosures Huang: Baxter: Research Funding; Biogen: Research Funding; Pfizer: Research Funding; Novartis: Other: support to attend meeting; Bio Products Laboratory: Other: Study Investigator. Akanezi:Bio Products Laboratory: Employment. Shapiro:BioMarin: Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; OPKO: Research Funding.

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Trends in Iron Overload over Past Two Decades: Results from the Natural History of Iron Burden Study with the SQUID Biosusceptometer

Blood ◽

10.1182/blood-2019-129701 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 961-961

Author(s):

Ashutosh Lal ◽

Roland Fischer ◽

Elliott Vichinsky ◽

Marcela Weyhmiller

Keyword(s):

Natural History ◽

Longitudinal Data ◽

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Iron Status ◽

Advisory Committees ◽

Liver Iron ◽

Non Invasive ◽

History Of

Established in 2002, the Iron Overload Program in Oakland relies on a biosusceptometer (Ferritometer®, model 5700, Tristan Technologies, San Diego, USA) utilizing low temperature SQUID technology to quantify liver iron concentration (LIC). The procedure is non-invasive and patients as young as 2 years can be been measured without sedation. The measurement and analysis are rapid (30 - 45 min) and the results have been validated against biopsy. Over 3500 measurements have been performed on 1055 patients at risk of iron overload. Longitudinal data were acquired under the natural history of iron burden by non-invasive measurement techniques study since November 2002. Patients were referred for liver iron assessment at intervals determined by their providers. Seventy-one patients had ≥10 measurements, 34 had ≥15 measurements, and 7 had ≥20 measurements. Over the course of the study, the average age at enrollment fell from 23 +/- 17 years (range 2 - 88 years) to 18 +/- 15 years (2 - 73 years). There was an increase in the proportion of patients with non-transfusion dependent thalassemia and those with iron overload from red cell transfusions associated with chemotherapy or stem cell transplantation. In comparison to the first five years (2003 - 2008) in the most recent five years (2014 - 2018) chelation has shifted from deferoxamine to deferasirox and there has been an increase in the simultaneous use of two chelators. We observed an overall decrease in mean LIC from 2400 to 1800 micrograms Fe/g liver wet weight (14.4 to 10.8 mg/g liver dry weight). Ferritin to LIC ratios were 0.46 in non-transfused thalassemia, 0.85 in intermittently transfused (< 7 mL/Kg/month), and 1.10 in transfusion-dependent (≥7 mL/Kg/month). A subgroup analysis of longitudinal data in transfusion-dependent thalassemia with multiple measurements was conducted. The mean (±s.d.) LIC decreased by 42% from 15.8 ± 10.2 at the first measurement to 9.2 ± 9.7 mg/g at the last visit. At the same time, mean ferritin decreased from 2629 to 2115 ng/mL, a change of 20%. In this group of patients ferritin levels now overestimate LIC by a significant amount (Figure). This reflects either a change in transfusion practices or the type of chelation. These results show a positive impact of oral chelators and combined chelation regimens leading to a significant improvement in iron overload in thalassemia. The development of organ complications from iron toxicity is expected to decrease, but there is a risk of over-chelation if ferritin is the sole measure of iron status. Liver biosusceptometry has been a valuable method to assess diverse conditions associated with iron overload and to monitor chelation treatment in patients across all ages. Figure Disclosures Lal: Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Terumo Corporation: Research Funding; Insight Magnetics: Research Funding; bluebird bio: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; La Jolla Pharmaceutical Company: Research Funding. Vichinsky:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Agios: Research Funding.

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Prophylactic Dosing of Anti-Inhibitor Coagulant Complex (FEIBA) Reduces Bleeding Frequency In Hemophilia A Patients with Inhibitors: Results of the Pro-FEIBA Study

Blood ◽

10.1182/blood.v116.21.720.720 ◽

2010 ◽

Vol 116 (21) ◽

pp. 720-720 ◽

Cited By ~ 4

Author(s):

Cindy A. Leissinger ◽

Eric Berntorp ◽

Chiara Biasioli ◽

Shannon Carpenter ◽

Hyejin Jo ◽

...

Keyword(s):

Clinical Trial ◽

Allergic Reaction ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Study Drug ◽

Advisory Committees ◽

Patient Age ◽

On Demand ◽

Bleeding Episodes

Abstract Abstract 720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Anecdotal reports and small case series suggest that regular doses of anti-inhibitor coagulant complex (AICC; FEIBA VH) may be effective in preventing bleeding episodes in patients with hemophilia A and inhibitors. The Pro-FEIBA study is the first prospective controlled clinical trial to study the efficacy of AICC in bleed prevention. Study Population and Design: The study was conducted in hemophilia A patients >2 years with a history of high-titer inhibitors who were using bypassing therapy for the treatment of bleeding episodes. Subjects on or planning immune tolerance therapy were excluded as were patients with thrombocytopenia or other bleeding disorders. This randomized, crossover study compared 6 months of AICC prophylactically dosed at 85 U/kg ± 15% on 3 nonconsecutive days per week (Prophy period) to 6 months of on-demand therapy (OD period) (target dose for the treatment of bleeds: 85 U/kg ± 15%). The 2 study periods were separated by a 3-month washout, during which time patients used on-demand therapy for bleeding. Patients were randomized to initially enter either the 6-month Prophy period or the 6-month OD period. Each patient then crossed-over to the alternate study period after a 3-month wash-out. Results: Thirty-four subjects were randomized; 26 subjects completed both study periods and were deemed evaluable per protocol (PP) for efficacy analysis of the primary outcome to compare bleeds in each 6-month treatment period. Eight subjects did not complete the study (1 patient in the Prophy treatment arm and 1 patient in the post-prophylaxis washout period died of complications associated with underlying illness and bleeding, 1 patient experienced an allergic reaction to study drug, 1 patient was lost to follow-up, and 4 patients withdrew from study). All randomized subjects were evaluated for safety. In the PP group, mean patient age was 26.9 years (median: 24.7; range: 2.8–67.9). In the total randomized group, mean patient age was 27.1 years (median: 28.7; range: 2.8–67.9). Of the 26 subjects who completed the study PP, 14 were randomized to enter the Prophy period first and then crossed-over to the OD period, while 12 subjects were initially randomized to enter the OD period and then crossed-over to the Prophy period. For the PP analysis, total bleeds and joint bleeds requiring treatment during the 2 study periods were compared (p-value is for the Wilcoxon signed-rank test of difference between OD and Prophy periods). In addition, bleeds for the 6-month period prior to enrollment were recorded retrospectively on study entry. Efficacy: Both total bleeds and joint bleeds were significantly reduced during the Prophy period as compared with the OD period (p < .0001) Table 1. There was no difference in bleed event rates based on randomization sequence (ie, no carry-over effect was detected when the Prophy period preceded the OD period). Safety: A total of 38 serious adverse events (SAEs) occurred, none of which was thrombotic in nature. One SAE was deemed by the study safety monitor to be related to the study drug (an allergic reaction). Otherwise, treatment was safe and well tolerated. Conclusion: These results in patients with hemophilia A and inhibitors show that AICC, dosed at 85 IU/kg +/− 15% given on 3 non-consecutive days each week was associated with a 62% reduction in all bleeds and a 61% reduction in joint bleeds as compared with on-demand therapy. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: This is a report of a clinical trial using the Anti-Inhibitor Coagulant Complex, FEIBA, as prophylactic therapy to prevent bleeding in hemophilia patients with inhibitors. FEIBA is not currently licensed for use in prophylaxis in the US. Berntorp:Baxter: Consultancy, Honoraria, Research Funding. Negrier:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rocino:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Windyga:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gringeri:Baxter: Consultancy, Honoraria, Research Funding; NovoNordisk: Honoraria.

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Safety and Efficacy of Nonacog Beta Pegol (N9-GP) for Prophylaxis and Treatment of Bleeding Episodes in Previously-Treated Patients with Hemophilia B: Results from an Extension Trial

Blood ◽

10.1182/blood.v124.21.2846.2846 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2846-2846

Author(s):

Guy Young ◽

Peter W. Collins ◽

Ramin Tehranchi ◽

Ampaiwan Chuansumrit ◽

Hideji Hanabusa ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Hemophilia B ◽

Phase 3 ◽

Advisory Committees ◽

Pivotal Phase ◽

Bleeding Rate ◽

On Demand ◽

Bleeding Episodes ◽

Extension Trial

Abstract Background: Prolongation technology has recently been employed to advance the treatment in hemophilia. Nonacog beta pegol (N9-GP) is a glycoPEGylated recombinant factor IX (rFIX) with a significantly extended half-life in hemophilia B adults (Negrier et al. Blood 2011), up to 111 h, as compared to currently available treatment options. The pivotal phase 3 trial, paradigm™2, demonstrated that the prophylactic protection of 40 U/kg N9-GP once weekly significantly reduced the risk of bleeding as well as successfully controlled the bleeding episodes (Collins et al. JTH (Suppl.2) 2013). It also demonstrated a potential to improve clinical outcomes, reduce joint damage and improve quality of life with fewer injections. The phase 3 extension trial, paradigm™4, was designed to investigate the safety and efficacy of long-term treatment with N9-GP in severe and moderately severe hemophilia B patients. Aims: The primary objective of this trial was to evaluate immunogenicity of N9-GP. Key secondary objectives were to assess therapeutic and prophylactic efficacy and safety of N9-GP. Methods: 71 hemophilia B patients above 12 years of age with ≤2% FIX activity, with no history of inhibitors, at least 150 exposures days (ED) to other FIX products, and who completed the pivotal phase 3 trial, paradigm™2, or the pivotal surgery trial, paradigm™3, were included. The trial was approved by local IRB/REC and all participants signed an informed consent before any trial related activity. Patients were allowed to change the treatment regimen at trial start or during the trial based on their clinical manifestation and investigator recommendation; options included on-demand treatment, or once weekly prophylaxis with 10 or 40 U/kg N9-GP. Immunogenicity was evaluated as the primary endpoint; incidence of inhibitory antibodies against FIX defined as titer ≥0.6 Bethesda Units (BU). Efficacy endpoints included frequency of bleeds among prophylaxis patients, hemostatic response to N9-GP infusion based on a 4-point categorical scale, as well as FIX activity as a surrogate marker. Results: A total of 71 patients were treated for at least 12 months, 67 of whom received a prophylactic regimen of N9-GP either 10 U/kg or 40 U/kg once weekly; there were considerable movements between treatment arms, with approximately one third of the patients moving from on-demand or 10 U/kg at the start of this extension trial, up to 40 U/kg, with a smaller proportion moving from 40 U/kg to 10 U/kg, or from 10 U/kg to on-demand. None of the patients in the trial developed inhibitors. There were no differences relating to adverse events or standard safety parameters between the treatment groups. In paradigm™4 a total of 94.6% of all bleeding episodes were successfully treated, with 87.9% of all bleeding episodes treated with a single infusion. Among patients on prophylaxis, a median (IQR) annualized bleeding rate of 1.1 (0.0 – 2.2) episodes per year was observed. There was a higher proportion of traumatic bleeding episodes in the patients on 40 U/kg N9-GP compared with patients on 10 U/kg N9-GP (57.1% vs. 28.6%, respectively), though the annualized bleeding rates were similar in both prophylactic groups, with median (IQR) ABR of 0.0 (0.0 – 1.0) and 0.0 (0.0 – 1.1) in 10 U/kg and 40 U/kg N9-GP, respectively. For spontaneous bleeds only, the median (IQR) annualized bleeding rate was 1.1 (0.0 – 2.2) and 0.0 (0.0 – 1.0) among patients treated with 10 U/kg and 40 U/kg N9-GP, respectively. Conclusion: The outcome of the trial confirmed the results from paradigm™2 that N9-GP appeared to have a safe and well-tolerated profile with good prophylactic protection and control of bleeding. Disclosures Young: Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: N9-GP is not yet FDA approved. Information provided will discuss phase 3 clinical trial data.. Collins:Novo Nordisk: Consultancy, Honoraria. Tehranchi:Novo Nordisk A/S: Employment, Shareholder Other. Chuansumrit:Novo Nordisk: Honoraria. Hanabusa:Baxter Healthcare, Novo Nordisk, Bayer, Pfizer, Biogen Idec and KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lentz:Novo Nordisk: Consultancy, Research Funding. Mahlangu:Biogen Idec, Novo Nordisk, Biotest: Speakers Bureau; Amgen, Bayer, Novo Nordisk, Pfizer, Genentech: Membership on an entity's Board of Directors or advisory committees; Bayer, Biogen Idec, Novo Nordisk: Research Funding. Mauser-Bunschoten:Sanquin, CSL Behring, Bayer, Baxter, Griffols, LFB, Novo Nordisk: Speakers Bureau; Sanquin, CSL Behring: Research Funding; Baxter: Consultancy; Novo Nordisk: Registration trial, Registration trial Other. Negrier:Novo Nordisk, Baxter, Bayer, CSL Behring, LFB and Pfizer: Consultancy, Honoraria, Research Funding. Oldenburg:Baxter, Bayer, Biogen Idec, Biotest, CSL-Behring, Grifols, Novo Nordisk, Octapharma, Swedish Orphan Biovitrum and Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Santagostino:Pfizer, Bayer, Baxter, Novo Nordisk, CSL Behring, Grifols, Biotest: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Zak:Novo Nordisk A/S: Employment.

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Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽

10.1182/blood-2019-128807 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3433-3433

Author(s):

Caitlin Siebenaller ◽

Madeline Waldron ◽

Kelly Gaffney ◽

Brian P. Hobbs ◽

Ran Zhao ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Smoking Status ◽

Consolidation Therapy ◽

Peripheral Vascular ◽

Consolidation Chemotherapy ◽

Advisory Committees ◽

History Of ◽

Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

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BCX9930, a Potent, Selective, Oral Factor D Inhibitor, Demonstrates Proof-of-Concept As Monotherapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽

10.1182/blood-2020-138838 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Austin Kulasekararaj ◽

Jacques Le Roux Malherbe ◽

Andrew McDonald ◽

Melanie Cornpropst ◽

Phil Collis ◽

...

Keyword(s):

South Africa ◽

Board Of Directors ◽

Research Funding ◽

Total Bilirubin ◽

Proof Of Concept ◽

Advisory Committees ◽

Clone Size ◽

The Past ◽

History Of ◽

Pre Treatment

INTRODUCTION: PNH, a rare, chronic, life-threatening disease, is characterized by hemolytic anemia due to uncontrolled activity of the complement alternative pathway (AP), bone marrow failure, and thrombosis. Inhibition of C5 by intravenously administered eculizumab and ravulizumab reduces intravascular hemolysis, but PNH red blood cells (RBCs) become opsonized and susceptible to extravascular hemolysis (Risitano et al, Blood 2009). Only approximately half of PNH patients become transfusion independent with eculizumab treatment (Hillmen et al, NEJM 2006). BCX9930 is a potent, selective, orally administered inhibitor of complement factor D. Inhibition of factor D may prevent both intravascular and extravascular hemolysis in PNH. In healthy subjects, BCX9930 showed linear pharmacokinetics and dose-related AP suppression, and was safe and generally well-tolerated over a wide dose range. Here we describe safety and laboratory data establishing proof-of-concept for BCX9930 monotherapy in PNH patients in Study BCX9930-101 (NCT04330534). METHODS: Ongoing Study BCX9930-101 includes an open-label, dose-ranging evaluation of BCX9930 in PNH subjects who may either be naïve to C5 inhibitors (and receive BCX9930 as monotherapy) or have an incomplete treatment response to eculizumab or ravulizumab (with BCX9930 added to existing treatment). Up to 4 sequential cohorts each use a forced titration design for the first 28 days (Figure 1). Subjects enrolled in South Africa can participate in an individualized 48-week extension if they derive benefit at Day 28. Clinical benefit from BCX9930 is evaluated using laboratory monitoring and symptom assessment. Safety and tolerability are evaluated via clinical and laboratory monitoring, causality of adverse events is assessed by investigators, and the study is overseen by an independent Data Monitoring Committee. Data from Cohort 1 through 28 days is reported; data from the extension and subsequent cohorts will be subsequently summarized as available. RESULTS: To date, four C5 inhibitor naïve PNH subjects in South Africa have enrolled in Cohort 1. These subjects had PNH for a median of 4.5 years; 2 subjects had a history of transfusions in the past year; 1 subject each had a history of aplastic anemia or major thrombosis. Pre-treatment lactate dehydrogenase (LDH), total bilirubin, hemoglobin (Hb), reticulocyte count, and RBC PNH Type III clone size ranged from 3.7-11.1 × ULN, 0.61-3.3 mg/dL, 6.1-11.6 g/dL, 0.13-0.29 × 106/µL, and 41.4%-88.6% respectively. Treatment over 28 days with 50 mg twice daily (BID; Days 1-14) and 100 mg BID (Days 15-28) of BCX9930 produced dose-dependent, clinically meaningful improvements across hemolysis biomarkers (Figure 2). Decreases were observed in LDH (4/4), reticulocytes (4/4), and total bilirubin (2/2 subjects with elevated pre-treatment values). Increases were observed in Hb (3/4) and PNH RBC clone size (4/4). One subject showed an initial response to BCX9930 50 mg BID, followed by worsening indicators of hemolysis temporally associated with an upper respiratory tract infection (URTI; onset on Day 7). With an increase in dose to 100 mg BID and resolution of the URTI, LDH and reticulocytes fell and Hb rose. All four subjects reported one or more PNH-associated symptoms, including hemoglobinuria, jaundice, fatigue, erectile dysfunction, headache and abdominal pain, prior to enrollment. With the exception of one subject with persistent hemoglobinuria, all symptoms resolved by Day 28 on BCX9930. Three subjects experienced moderate headache that resolved in < 3 days after initiating BCX9930. One subject developed a rash during treatment with amoxicillin for an URTI; the rash resolved while continuing BCX9930 dosing. One subject on concomitant chronic corticosteroids and azathioprine had an unrelated fatal serious adverse event of disseminated varicella during the study extension. Based on review of safety data, Cohort 2 opened at doses of 200 mg BID and 400 mg BID and, in the 3 subjects who continued into the extension, the dose was titrated to ≥ 200 mg BID. CONCLUSIONS: Oral BCX9930 elicited rapid changes in laboratory parameters indicative of reduced hemolysis and clinical benefit and was safe and generally well-tolerated over a 28-day dosing interval. These interim results establish proof of concept for monotherapy with BCX9930 in the treatment of C5-inhibitor naïve PNH patients and support evaluation of higher doses. Disclosures Kulasekararaj: Alexion:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Ra Pharma:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;BioCryst Pharmaceuticals, Inc.:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Apellis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau.Malherbe:Key Oncologics:Honoraria, Other: Conference sponsor;Novartis:Other: Conference sponsor;Astellas:Honoraria, Other: Conference sponsor;Takeda:Consultancy;Acino:Honoraria;Shire:Other: Conference sponsor;BioCryst Pharmaceuticals, Inc.:Consultancy;Janssen:Consultancy, Honoraria, Other: Conference sponsor;Roche:Honoraria, Other: Conference sponsor.McDonald:venetoclax advisory board in South Africa (in CLL context):Consultancy;Alberts Cellular Therapy:Current Employment.Cornpropst:BioCryst Pharmaceuticals, Inc.:Current Employment.Collis:BioCryst Pharmaceuticals, Inc.:Current Employment.Davidson:BioCryst Pharmaceuticals, Inc.:Current Employment.Chen:BioCryst Pharmaceuticals, Inc.:Current Employment.Tower:BioCryst Pharmaceuticals, Inc.:Current Employment.Gesty-Palmer:BioCryst Pharmaceuticals, Inc.:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Sheridan:BioCryst Pharmaceuticals, Inc.:Current Employment.Risitano:Alexion:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Alnylam:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Pfizer:Speakers Bureau;Achillion:Membership on an entity's Board of Directors or advisory committees;Apellis:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Biocryst:Membership on an entity's Board of Directors or advisory committees;RA pharma:Research Funding;Amyndas:Consultancy;Samsung:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;Jazz:Speakers Bureau.

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Assessing the Safety of Various VWF Regimens in Patients with Clinically Severe VWD: A Natural History Study

Blood ◽

10.1182/blood-2019-128318 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1132-1132

Author(s):

Robert F. Sidonio ◽

Angela C. Weyand ◽

Dunlei Cheng ◽

Crystal Watson

Keyword(s):

Board Of Directors ◽

Study Design ◽

Real World ◽

Research Funding ◽

Laboratory Data ◽

Severe Bleeding ◽

Advisory Committees ◽

On Demand ◽

Type 3 ◽

Von Willebrand

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder in humans affecting up to 1% of the population, while symptomatic prevalence is likely closer to 0.1%. A deficiency of von Willebrand factor (VWF) can be quantitative (type 1 or type 3) or qualitative (type 2) and lead to a bleeding diathesis of variable intensity roughly correlating with functional activity. Diagnosis can be challenging due to variable penetrance and large influence of multiple pre-analytic variables and a wide testing coefficient of variation. Treatment for VWD is focused on replacement of defective or deficient VWF with a plasma-derived or recombinant VWF-containing product, release and elevation of endogenous stores of VWF with Desmopressin (DDAVP), or prevention of premature fibrinolysis with an antifibrinolytic, such as aminocaproic acid. Although there is relative consensus on the management of mild VWD, there is scarce literature about the optimal treatment of patients with severe disease, especially in regard to factor replacement. Real World evidence for the use of primary (prior to significant bleeding) or secondary (following development of significant bleeding) prophylaxis is lacking with the majority of studies relying heavily on retrospective data. Additionally, ongoing VWD prophylaxis studies typically only allow participants to enroll if they previously have not been on prophylaxis, limiting our ability to learn about this growing population of patients. Study Design and Methods: Approximately 1,900 VWD patients were identified in the ATHNdataset with a VWF:Ag or VWF:RCo of ≤ 30%, with ~170 of these on prophylaxis. This group, in addition to those VWD patients with clinically significant bleeding and ≤ 40% of normal VWF:Ag or VWF:RCo, provide a potential unmet opportunity to examine prophylaxis and treatment patterns. Furthermore, a standardized laboratory assessment (including a standardized diagnostic battery, genetic evaluation of VWF gene, and inhibitor testing) will provide significant enrichment of the ATHNdataset by fully characterizing patients that are highly likely to utilize factor concentrates. Inclusion criteria are patients with severe VWD defined as type 3 VWD, or VWF:RCo, VWF:GP1bM or VWF:Ag≤ 30%, patients with clinically severe VWD as defined by VWF:Rco, VWF:GP1bM or VWF:Ag ≤ 40% with severe bleeding phenotype requiring recurrent use of factor concentrates, and co-enrollment in the ATHNdataset. Patients with platelet-type or acquired VWD are excluded. The primary objective is to assess the safety of various VWF regimens for different indications (on-demand, surgery, and prophylaxis) in adult and pediatric patients with clinically severe VWD. Safety is measured by the number of reported events as defined by the European Haemophilia Safety Surveillance (EUHASS) program. Secondary objectives are to enrich and analyze data from clinically severe congenital VWD patients by collecting laboratory data; to establish sub-studies for patients who are treated with VWF products on demand or who have started on or switched to a particular VWF containing product; to evaluate the use of factor replacement as prophylaxis in a cohort of severe VWD participants over 6 month time periods; to describe bleeding events, changes in overall bleeding, and annualized bleed rate as measured by the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) and if applicable the Pictorial Bleed Assessment Chart (PBAC); and to describe real-world effectiveness of VWD treatment as measured by health care utilization and quality of life measures (PROMIS® and V-WIQ questionnaires). Descriptive statistics will be calculated to analyze the primary and secondary outcomes. For each categorical variable, its frequency and percentage will be reported. In terms of a continuous measurement, its mean, median, standard deviation, interquartile range, minimum, and maximum values will be disclosed. The study will attempt to enroll a target number of at least 50 participants who are receiving VONVENDI but will not mandate the use of VONVENDI. More study design details are outlined in Table 1. Disclosures 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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